Processes for preparing dihydropyrimidine derivatives and intermediates thereof

ABSTRACT

The present invention relates to processes for preparing a dihydropyrimidine derivative having Formula (I) or a tautomer thereof having Formula (Ia), as well as a intermediate thereof. The processes of the invention have simple operation, high optical purity of product, high yield and convenient work-up, which is suitable for industrial production.

CROSS-REFERENCE TO RELATED APPLICATIONS

This is a U.S. national stage application of the International Patent Application No. PCT/CN2014/092401, filed Nov. 27, 2014, which claims priorities to Chinese Patent Application No. 201310636920.8, filed Nov. 27, 2013, and No. 201410121009.8, filed Mar. 27, 2014, all of which are incorporated herein by reference in their entirety.

FIELD

The invention refers to a chemical medicine field. Specifically, the invention relates to processes for preparation of dihydropyrimidine derivatives and dihydropyrimidine intermediates thereof.

BACKGROUND

The hepatitis B virus belongs to the family of hepadnaviridae. It can cause acute and/or persistent or progressive chronic diseases. Many other clinical manifestations in the pathological morphology can be also caused by HBV—in particular chronic hepatitis, cirrhosis and hepatocellular carcinoma. Additionally, coinfection with hepatitis D virus may have adverse effects on the progress of the disease.

The conventional medicaments approved to be used for treating chronic hepatitis are interferon and lamivudine. However, the interferon has just moderate activity but has an adverse side reaction. Although lamivudine has good activity, its resistance develops rapidly during the treatment and relapse effects often appear after the treatment has stopped. The IC₅₀ value of lamivudine (3-TC) is 300 nM (Science, 2003, 299, 893-896).

PCT Publication No. WO2008154817 discloses a series of compounds used for preventing, managing, treating or lessening a viral disease in a patient, particularly HBV infection or a disease caused by HBV infection. The patent also provides the processes for preparation of specific compounds, such as ethyl 4-(2-bromo-4-fluorophenyl)-6-(morpholinomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate as shown in Formula (Ib).

PCT Publication No. WO2008009210 discloses a series of optically pure compounds and preparation method thereof, which used for preventing, managing, treating or lessening an acute or chronic viral disease in a patient, particularly an acute or chronic HBV disease. The patent also provides the processes for preparation of specific compounds, such as, (R)-ethyl 4-(2-chloro-4-fluorophenyl)-6-methyl-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate.

Dihydropyrimidine derivatives can be prepared by several methods described in prior arts, such as patents WO1999054329, WO2008154817, WO2001068641 and WO2010069147, and so on. But the process for preparing an optically pure dihydropyrimidine compound disclosed herein has not yet been published.

SUMMARY

The present invention refers to a process for preparing a dihydropyrimidine compound having Formula (I), or a tautomer thereof having Formula (Ia),

wherein each R¹ is F; R² is Cl or Br;

R³ is C₁₋₄ alkyl;

Z is —O—, —S—, —S(═O)_(t)—, or —N(R⁴)—;

Y is —O—, —S—, —S(═O)_(t)—, —(CH₂)_(q)—, or —N(R⁵)—;

each t and q is independently 0, 1, or 2;

each of R⁴ and R⁵ is independently H or C₁₋₄alkyl;

each R⁶ is independently H, deuterium, halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, amino, C₁₋₄alkylamino, C₁₋₄alkoxy, nitro, triazolyl, tetrazyl, —(CR⁷R^(7a))_(m)—OH, —S(═O)_(q)OR^(8a), —(CR⁷R^(7a))_(m)—S(═O)_(q)N(R^(8a))₂, —(CR⁷R^(7a))_(t)—N(R^(8a))₂, —(CR⁷R^(7a))_(m)—C(═O)O—R⁸, —(CR⁷R^(7a))_(m)—C(═O)O—(CR⁷R^(7a))_(m)—OC(═O)O—R⁸, —(CR⁷R^(7a))_(m)—C(═O)O—(CR⁷R^(7a))_(m)—OC(═O)—R⁸, —(CR⁷R^(7a))_(m)—C(═O)O—(CR⁷R^(7a))_(m)—C(═O)O—R⁸, —(CR⁷R^(7a))_(m)—OC(═O)—R⁸, or —(CR⁷R^(7a))_(m)—C(═O)—N(CR⁸R^(8a));

each R^(7a) and R⁷ is independently H, halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, —(CH₂)_(m)—OH, or —(CH₂)_(m)—C(═O)O—R⁸; or R^(7a) and R⁷, together with the carbon atom to which they are attached, form a C₃₋₆ cycloalkyl group, C₂₋₉ heterocyclyl group, or —(C═O)—;

each R⁸ and R^(8a) is independently H, C₁₋₄alkyl, amino-C₁₋₄-alkyl, C₁₋₄ alkoxy, C₁₋₆alkyl-S(═O)_(q)—, C₆₋₁₀ aryl, C₁₋₉ heteroaryl, C₃₋₆ cycloalkyl, C₂₋₉ heterocyclyl, C₆₋₁₀ aryl-C₁₋₆-alkyl, C₁₋₉ heteroaryl-C₁₋₆-alkyl, C₃₋₆ cycloalkyl-C₁₋₄-alkyl, C₂₋₉ heterocyclyl-C₁₋₆-alkyl, C₂₋₉ heterocyclyl-S(═O)_(q)—, C₁₋₉ heteroaryl-S(═O)_(q)—, C₃₋₆ cycloalkyl-S(═O)_(q)—, C₆₋₁₀ aryl-S(═O)_(q)—, —(CH₂)_(m)—OH, —(CH₂)_(m)—C(═O)O—(CH₂)_(m)—H— or —(CH₂)_(m)—OC(═O)—(CH₂)_(m)—H;

each R⁹ is independently H, halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkylthio, C₃₋₆ cycloalkyl, —(CR⁷R^(7a))_(m)—C(═O)—N(R⁸R^(8a)), or —(CR⁷R^(7a))_(m)—C(═O)O—R⁸;

R¹⁰ is H or deuterium;

n is 0, 1, 2, 3, 4, or 5;

each m is independently 0, 1, 2, 3, or 4;

f is 1, 2, 3, or 4; and

j is 0, 1, or 2;

Two preparation methods of a dihydropyrimidine compound having Formula (I) or a tautomer thereof having Formula (Ia) are described in the following schemes,

Method One

A dihydropyrimidine compound having Formula (I) or a tautomer thereof having Formula (Ia) can be prepared by the general synthetic method one illustrated in Scheme 1, wherein R¹, R², Z, R⁹, j, f, R⁶, n, Y and R¹⁰ are as defined herein; wherein R^(3a) is H or C₁₋₃ alkyl; R^(3b) is C₁₋₆ alkoxy, C₁₋₆ alkylamino, C₃₋₆ cycloalkoxy, C₃₋₆ cycloalkylamino, C₁₋₆ alkyl-C₃₋₆-cycloalkoxy, C₆₋₁₀ arylamino, benzylamino or benzyloxy. The method one comprises the following steps of: reacting a compound (VIII) with a compound (IX) to obtain a compound (IV); step (A): reacting a compound (II) or a salt thereof with a compound (III) and the compound (IV) to obtain a compound (V) (according to some embodiments of the present invention, the reaction of the step (A) may be an one-pot reaction); step (B): halogenating the compound (V) to form a halide; and then reacting the halide with a compound (VI) or a salt thereof to obtain a compound (VII); step (C): forming a compound (I), or compound (Ia) from the compound (VII) in the presence of a base (according to some embodiments of the present invention, the reaction of the step (C) may be a transesterification).

Method Two

A dihydropyrimidine compound having Formula (I) or a tautomer thereof having Formula (Ia) can be prepared by the general synthetic method two illustrated in Scheme 2, wherein R¹, R², Z, R⁹, j, f, R⁶, n, Y, R¹⁰, R^(3a) and R^(3b) are as defined herein. The method two comprises the following steps of: step (1): reacting the compound (V) in the presence of a base to obtain a compound (X) (according to some embodiments of the present invention, the reaction of the step (1) may be a transesterification); step (2): halogenating the compound (X) to form a halide, and then reacting the halide with a compound (VI) to obtain a compound (I) or compound (Ia).

The method one in scheme 1 and method two in scheme 2 comprises introducing a new chiral center to the mother nucleus of the compound, splitting the diastereomers based on the difference in the solubility of the diastereomers, and then removing the new chiral center from the mother nucleus by transesterification, then a compound may be obtained and in some embodiments of the present invention, the obtained compound may beoptically pure. These methods have advantages of convenient work-up, high optical purity of product and high yield. In addition, the process of the invention possesses the advantages of cheap raw material, mild reaction conditions, simplified operational procedure, safety and controllable, and easy industrialization.

The present invention also refers to a compound comprising a dihydropyrimidine compound of Formula (V), or a tautomer thereof having Formula (V1), or a salt thereof, or a combination thereof,

wherein R¹, R², f, Z, R⁹, j, R¹⁰, R^(3a) and R^(3b) are as defined herein.

In one aspect, provided herein is a process for preparing a dihydropyrimidine compound having Formula (I), or a tautomer thereof having Formula (Ia) (such as the method one described in scheme 1),

wherein each R¹ is F; R² is Cl or Br;

R³ is C₁₋₄ alkyl;

Z is —O—, —S—, —S(═O)_(t)—, or —N(R⁴)—;

Y is —O—, —S—, —S(═O)_(t)—, —(CH₂)_(q)—, or —N(R⁵)—;

each t and q is independently 0, 1, or 2;

each of R⁴ and R⁵ is independently H, or C₁₋₄alkyl;

each R⁶ is independently H, deuterium, halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, amino, C₁₋₄alkylamino, C₁₋₄alkoxy, nitro, triazolyl, tetrazyl, —(CR⁷R^(7a))_(m)—OH, —S(═O)_(q)OR^(8a), —(CR⁷R^(7a))_(m)—S(═O)_(q)N(R^(8a))₂, —(CR⁷R^(7a))_(t)—N(R^(8a))₂, —(CR⁷R^(7a))_(m)—C(═O)O—R⁸, —(CR⁷R^(7a))_(m)—C(═O)O—(CR⁷R^(7a))_(m)—OC(═O)O—R⁸, —(CR⁷R^(7a))_(m)—C(═O)O—(CR⁷R^(7a))_(m)—OC(═O)—R⁸, —(CR⁷R^(7a))_(m)—C(═O)O—(CR⁷R^(7a))_(m)—C(═O)O—R⁸, —(CR⁷R^(7a))_(m)—OC(═O)—R⁸, or —(CR⁷R^(7a))_(m)—C(═O)—N(CR⁸R^(8a));

each R^(7a) and R⁷ is independently H, halo, C₁₋₄alkyl, C₁₋₄haloalkyl, —(CH₂)_(m)—OH, or —(CH₂)_(m)—C(═O)O—R⁸; or R^(7a) and R⁷, together with the carbon atom to which they are attached, form a C₃₋₆ cycloalkyl group, C₂₋₉ heterocyclyl group, or —(C═O)—;

each R⁸ and R^(8a) is independently H, C₁₋₄ alkyl, amino-C₁₋₄-alkyl, C₁₋₄ alkoxy, C₁₋₆ alkyl-S(═O)_(q)—, C₆₋₁₀ aryl, C₁₋₉ heteroaryl, C₃₋₆ cycloalkyl, C₂₋₉ heterocyclyl, C₆₋₁₀ aryl-C₁₋₆-alkyl, C₁₋₉ heteroaryl-C₁₋₆-alkyl, C₃₋₆ cycloalkyl-C₁₋₄-alkyl, C₂₋₉ heterocyclyl-C₁₋₆-alkyl, C₂₋₉ heterocyclyl-S(═O)_(q)—, C₁₋₉ heteroaryl-S(═O)_(q)—, C₃₋₆ cycloalkyl-S(═O)_(q)—, C₆₋₁₀ aryl-S(═O)_(q)—, —(CH₂)_(m)—OH, —(CH₂)_(m)—C(═O)O—(CH₂)_(m)—H, or —(CH₂)_(m)—OC(═O)—(CH₂)_(m)—H;

each R⁹ is independently H, halo, C₁₋₄alkyl, C₁₋₄haloalkyl, C₁₋₄alkylthio, C₃₋₆ cycloalkyl, —(CR⁷R^(7a))_(m)—C(═O)—N(R⁸R^(8a)) or —(CR⁷R^(7a))_(m)—C(═O)O—R⁸;

R¹⁰ is H or deuterium;

n is 0, 1, 2, 3, 4, or 5;

each m is independently 0, 1, 2, 3 or 4;

f is 1, 2, 3, or 4; and

j is 0, 1, or 2;

wherein the process comprises the steps of:

step (A): reacting an amidine compound of Formula (II), or a salt thereof with an aldehyde compound of Formula (III) and a compound of Formula (IV) to obtain a compound (V) (according to some embodiments of the present invention, the reaction of step (A) may be an one-pot reaction),

wherein R^(3b) is C₁₋₆ alkoxy, C₁₋₆ alkylamino, C₃₋₆ cycloalkoxy, C₃₋₆ cycloalkylamino, C₁₋₆ alkyl-C₃₋₆-cycloalkoxy, C₆₋₁₀ arylamino, benzylamino, or benzyloxy; and

R^(3a) is H or C₁₋₃ alkyl;

step (B): halogenating the compound of Formula (V) to produce a halide; reacting the halide with a compound of Formula (VI), or a salt thereof to obtain a compound of Formula (VII),

step (C): forming a compound of Formula (I), or Formula (Ia) from the compound of Formula (VII) by means of a transesterification, and the transesterification may be carried out in the presence of a base.

In some embodiments, the dihydropyrimidine compound having Formula (I-1), or a tautomer thereof having Formula (Ia-1),

wherein each R⁶ is independently H, halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, amino, C₁₋₄alkylamino, C₁₋₄alkoxy, nitro, triazolyl, tetrazyl, —(CR⁷R^(7a))_(m)—OH, —S(═O)_(q)OR^(8a), —(CR⁷R^(7a))_(m)—S(═O)_(q)N(R^(8a))₂, —(CR⁷R^(7a))_(t)—N(R^(8a))₂, —(CR⁷R^(7a))_(m)—C(═O)O—R⁸, —(CR⁷R^(7a))_(m)—C(═O)O—(CR⁷R^(7a))_(m)—OC(═O)O—R⁸, —(CR⁷R^(7a))_(m)—C(═O)O—(CR⁷R^(7a))_(m)—OC(═O)—R⁸, —(CR⁷R^(7a))_(m)—C(═O)O—(CR⁷R^(7a))_(m)—C(═O)O—R⁸, —(CR⁷R^(7a))_(m)—OC(═O)—R⁸, or —(CR⁷R^(7a))_(m)—C(═O)—N(R⁸R^(8a)); and

each R^(7a) and R⁷ is independently H, C₁₋₄alkyl, C₁₋₄ haloalkyl, —(CH₂)_(m)—OH, or —(CH₂)_(m)—C(═O)O—R⁸;

each R¹, R², R³, Z, n, Y, m, q, R^(8a), t and R⁸ is as defined herein.

According to embodiments of present invention, the method one for preparing the dihydropyrimidine compound having Formula (I-1), or a tautomer thereof having Formula (Ia-1) comprises the steps of:

step (A): reacting an amidine compound of Formula (II-1), or a salt thereof with an aldehyde compound of Formula (III-1) and the compound of Formula (IV) to obtain a compound (V-1) (according to some embodiments of the present invention, the reaction of the step (A) may be an one-pot reaction).

wherein R^(3a) is as defined herein; R^(3b) is C₁₋₆ alkoxy, C₁₋₆alkylamino, benzylamino, or benzyloxy;

step (B): halogenating the compound of Formula (V-1) to form a halide; and then reacting the halide with a compound of Formula (VI), or a salt thereof to obtain a compound of Formula (VII-1);

step (C): forming a compound of Formula (I-1), or Formula (Ia-1) from the compound of Formula (VII-1) by means of a transesterification, wherein the transesterification may be carried out in the presence of a base.

In some embodiments, the dihydropyrimidine compound having Formula (I-2), or a tautomer thereof having Formula (Ia-2),

wherein R¹ is F; and R² is Cl or Br; R³, Z, n, R⁶ and Y are as defined herein.

According to embodiments of the present invention, the method one for preparing the dihydropyrimidine compound having Formula (I-2), or a tautomer thereof having Formula (Ia-2) comprises the steps of:

step (A): reacting an amidine compound of Formula (II-1), or a salt thereof with an aldehyde compound of Formula (III-2) and the compound of Formula (IV) to obtain a compound (V-2) (according to some embodiments of the present invention, the reaction of the step (A) may be an one-pot reaction),

wherein R^(3b) and R^(3a) are as defined in Formula (V-1) disclosed herein;

step (B): halogenating the compound of Formula (V-2) to a halide; and then reacting the halide with a compound of Formula (VI), or a salt thereof to obtain a compound of Formula (VII-2),

step (C): forming a compound of Formula (I-2), or Formula (Ia-2) from the compound of Formula (VII-2) by means of a transesterification, wherein the transesterification may be carried out in the presence of a base.

According to some embodiments of the present invention, in the method one disclosed herein, in some embodiments, the R³ is methyl, ethyl, propyl, isopropyl, tert-butyl, or butyl; Z is —O—, —S—, or —N(CH₃)—; Y is —O—, —S—, —S(═O)₂, or —(CH₂)_(q)—; each R⁶ is independently H, halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, amino, C₁₋₄alkylamino, C₁₋₄ alkoxy, nitro, triazolyl, tetrazyl, —(CR⁷R^(7a))_(m)—OH, —(CR⁷R^(7a))_(m)—C(═O)O—R⁸, —(CR⁷R^(7a))_(t)—N(R^(8a))₂, —S(═O)_(q)OR^(8a), —(CR⁷R^(7a))_(m)—S(═O)N(R^(8a))₂, —(CR⁷R^(7a))_(m)—C(═O)O—(CR⁷R^(7a))_(m)—OC(═O)O—R⁸, —(CR⁷R^(7a))_(m)—C(═O)O—(CR⁷R^(7a))_(m)—OC(═O)—R⁸, —(CR⁷R^(7a))_(m)—C(═O)O—(CR⁷R^(7a))_(m)—C(═O)O—R⁸, —(CR⁷R^(7a))_(m)—OC(═O)—R⁸, or —(CR⁷R^(7a))_(m)—C(═O)N(R⁸R^(8a)); each R^(7a) and R⁷ is independently H, methyl, ethyl, trifluoromethyl, —(CH₂)_(m)—OH, or —(CH₂)_(m)—C(═O)O—R⁸; each R⁸ and R^(8a) is independently H, methyl, ethyl, propyl, isopropyl, aminomethyl, methoxy, C₁₋₄ alkyl-S(═O)₂—, phenyl, pyridyl, thiazolyl, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyrimidinyl, pyridazinyl, diazolyl, triazolyl, tetrazolyl, thienyl, pyrazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyrazinyl, pyranyl, triazinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyl-S(═O)₂—, cyclobutyl-S(═O)₂—, cyclopentyl-S(═O)₂—, cyclohexyl-S(═O)₂—, naphthyl-S(═O)₂—, phenyl-S(═O)₂—, —(CH₂)_(m)—OH, —(CH₂)_(m)—C(═O)O—(CH₂)_(m)—H, or —(CH₂)_(m)—OC(═O)—(CH₂)_(m)—H; R^(3b) is methoxy, ethoxy, isopropoxy, propoxy, tert-butoxy, n-butoxy, 1-methylpropoxy, n-pentyloxy, n-hexyloxy, methylamino, ethylamino, isopropylamino, propylamino, tert-butylamino, n-butylamino, 1-methylpropylamino, n-pentylamino, n-hexylamino, benzylamino, or benzyloxy; and R^(3a) is H, methyl, ethyl, isopropyl, or propyl.

According to some embodiments of the present invention, in the method one disclosed herein, the reaction in step (A) is performed at a temperature from 25° C. to 154° C. In some other embodiments, the reaction in step (A) is performed at a temperature from 60° C. to 100° C.

According to embodiments of present invention, in the method one disclosed herein, the reaction in step (A) is performed at a temperature, in some embodiments, the reaction temperature is from 25° C. to 154° C. In other embodiments, the reaction temperature is from 30° C. to 154° C. In still other embodiments, the reaction temperature is from 60° C. to 100° C. In yet other embodiments, the reaction temperature is 25° C., 30° C., 40° C., 56° C., 60° C., 64° C., 65° C., 77° C., 78° C., 80° C., 82° C., 100° C., 110° C., 120° C., 130° C., 140° ° C. or 154° C.

According to some embodiments of the present invention, in the method one disclosed herein, the step (A) further comprises a step of cooling the resulting compound of Formula (V) of step (A) to obtain a solid compound of Formula (V) at a cooling temperature from −40° C. to 40° C. In some other embodiments, the cooling temperature is from 25° C. to 40° C. In some embodiments, the cooling is performed for a period of from 0 hour to 24 hours. In some other embodiments, the cooling is performed for from 1 minute to 24 hours. In still other embodiments, the cooling is performed for from 1 hour to 8 hours.

According to some embodiments of the present invention, in the method one disclosed herein, the cooling in step (A) is carried out at a temperature, in some embodiments, the cooling temperature is from −50° C. to 60° C. In other embodiments, the cooling temperature is from −40° C. to 40° C. In other embodiments, the cooling temperature is from −20° C. to 40° C. In other embodiments, the cooling temperature is from −10° C. to 40° C. In still other embodiments, the cooling temperature is from 10° C. to 40° C. In yet other embodiments, the cooling temperature is from 25° C. to 40° C. In yet other embodiments, the cooling temperature is −50° C., −40° C., −30° C., −20° C., −15° C., −10° C., −5° C., 0° C., 5° C., 10° C., 15° C., 20° C., 25° C., 30° C., 35° C., 40° C., 50° C. or 60° C.

According to some embodiments of the present invention, in the method one disclosed herein, the cooling temperature in step (A) is kept for a period of time, in some embodiments, the period of time is from 0 hour to 30 hours. In other embodiments, the period of time is from 0 hour to 24 hours. In other embodiments, the period of time is from 1 minute to 24 hours. In other embodiments, the period of time is from 1 hour to 12 hours. In other embodiments, the period of time is from 1 hour to 8 hours. In other embodiments, the period of time is from 1 hour to 6 hours. In other embodiments, the period of time is from 3 hours to 8 hours. In still other embodiments, the period of time is from 3 hours to 6 hours. In yet other embodiments, the period of time is 0 hour, 1 minute, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 10 hours, 12 hours, 14 hours, 16 hours, 18 hours, 20 hours, 22 hours, 24 hours or 30 hours.

According to some embodiments of the present invention, in the method one disclosed herein, the amidine compound of Formula (II) reacts with the aldehyde compound of Formula (III) and the compound of Formula (IV) in a first organic solvent. In some embodiments, the first organic solvent is applied in an amount of 0 equivalent to 80 equivalents per 1 equivalent by weight of the amidine compound of Formula (II), or a salt thereof. In some other embodiments, the first organic solvent is applied in an amount of 1 equivalent to 20 equivalents per 1 equivalent by weight of the amidine compound of Formula (II), or a salt thereof.

According to some embodiments of the present invention, in the method one disclosed herein, the first organic solvent in step (A) is applied in an amount, in some embodiments, the amount is about 0 equivalent to 80 equivalents per 1 equivalent by weight of an amidine compound of Formula (II), or Formula (II-1), or a salt thereof. In other embodiments, the amount is about 1 equivalent to 80 equivalents per 1 equivalent by weight of an amidine compound of Formula (II), or Formula (II-1), or a salt thereof. In other embodiments, the amount is about 1 equivalent to 20 equivalents per 1 equivalent by weight of an amidine compound of Formula (II), or Formula (II-1), or a salt thereof. In other embodiments, the amount is about 2 equivalents to 20 equivalents per 1 equivalent by weight of an amidine compound of Formula (II), or Formula (II-1), or a salt thereof. In other embodiments, the amount is about 1 equivalent to 10 equivalents per 1 equivalent by weight of an amidine compound of Formula (II), or Formula (II-1), or a salt thereof. In still other embodiments, the amount is about 3 equivalents to 10 equivalents per 1 equivalent by weight of an amidine compound of Formula (II), or Formula (II-1), or a salt thereof. In yet other embodiments, the amount is about 0, 1, 2, 2.5, 3, 4, 4.5, 5, 6, 7, 8, 10, 12, 15, 16, 18, 20, 30, 40, 50, 60, 70 or 80 equivalents per 1 equivalent by weight of an amidine compound of Formula (II), or Formula (II-1), or a salt thereof.

According to some embodiments of the present invention, in the method one disclosed herein, the step (A) further comprises a step of purifying the solid compound of Formula (V). In some embodiments, the solid compound of Formula (V) is purified by at least one of the following methods: (1) trituration; (2) recrystallization; (3) washing.

According to some embodiments of the present invention, the purification is carried out in a second organic solvent. In some embodiments, the second organic solvent is applied in an amount of 2 equivalents to 20 equivalents per 1 equivalent by weight of the amidine compound of Formula (II), or a salt thereof.

According to some embodiments of the present invention, in the method one disclosed herein, the trituration is carried out at a temperature from −20° C. to 50° C. In some embodiments, the trituration is carried out at a temperature from 5° C. to 40° C.

According to some embodiments of the present invention, in the method one disclosed herein, the recrystallization comprises a crystallization process at a temperature from −30° C. to 40° C. In some embodiments, the crystallization process is carried out at a temperature from 0° C. to 40° C. In some embodiments, the recrystallization comprises a crystallization process of from 1 hour to 20 hours. In some other embodiments, the recrystallization comprises a crystallization process of from 1 hour to 12 hours.

According to some embodiments of the present invention, in the method one disclosed herein, the washing is performed at a temperature from 0° C. to 30° C.

According to some embodiments of the present invention, in the method one disclosed herein, the compound of Formula (V), Formula (V-1), or Formula (V-2) obtained in step (A) is further purified before step (B). In some embodiments, the compound is further purified by triturating with a second organic solvent. In some embodiments, the trituration is carried out at a temperature from −20° C. to 50° C. In other embodiments, the trituration temperature is from 5° C. to 40° C. In other embodiments, the trituration temperature is from 10° C. to 40° C. In still other embodiments, the trituration temperature is from 25° C. to 40° C. In yet other embodiments, the trituration temperature is −20° C., −10° C., 0° C., 5° C., 10° C., 25° C., 30° C., 35° C., 40° C. or 50° C.

According to some embodiments of the present invention, in the method one disclosed herein, the compound of Formula (V), Formula (V-1), or Formula (V-2) obtained in step (A) is further purified before step (B). In some embodiments, the compound is further purified by recrystallizing from a second organic solvent. In some embodiments, the recrystallization has a crystallization process at a temperature from −30° C. to 50° C. In other embodiments, the crystallization temperature is from −30° C. to 40° C. In still other embodiments, the crystallization temperature is from −20° C. to 40° C. In yet other embodiments, the crystallization temperature is from −20° C. to 30° C. In other embodiments, the crystallization temperature is from 0° C. to 40° C. In other embodiments, the crystallization temperature is from 0° C. to 30° C. In other embodiments, the crystallization temperature is −30° C., −20° C., −10° C., 0° C., 5° C., 10° C., 15° C., 20° C., 25° C., 30° C., 35° C., 40° C. or 50° C. In some embodiments, the recrystallization has a crystallization process taking a period of time from 1 hour to 20 hours. In other embodiments, the period of time is from 2 hours to 18 hours. In other embodiments, the period of time is from 1 hour to 12 hours. In still other embodiments, the period of time is from 4 hour to 12 hours. In yet other embodiments, the period of time is 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 12 hours, 14 hours, 16 hours, 18 hours or 20 hours.

According to some embodiments of the present invention, in the method one disclosed herein, the compound of Formula (V), Formula (V-1), or Formula (V-2) obtained in step (A) is further purified before step (B). In some embodiments, the compound is further purified by washing with a second organic solvent. In some embodiments, the washing is performed at a temperature from 5° C. to 40° C. In other embodiments, the washing temperature is from 0° C. to 30° C. In still other embodiments, the washing temperature is −20° C., −10° C., 0° C., 10° C., 20° C., 25° C., 30° C., 35° C., 40° C. or 50° C.

According to some embodiments of the present invention, in the method one disclosed herein, the second organic solvent used in the further purification before step (B) is applied in an amount, in some embodiments, the amount is about 0 equivalent to 20 equivalents per 1 equivalent by weight of an amidine compound of Formula (II), or Formula (II-1), or a salt thereof. In other embodiments, the amount is about 1 equivalent to 20 equivalents per 1 equivalent by weight of an amidine compound of Formula (II), or Formula (II-1), or a salt thereof. In other embodiments, the amount is about 2 equivalents to 20 equivalents per 1 equivalent by weight of an amidine compound of Formula (II), or Formula (II-1), or a salt thereof. In other embodiments, the amount is about 2 equivalents to 15 equivalents per 1 equivalent by weight of an amidine compound of Formula (II), or Formula (II-1), or a salt thereof. In still other embodiments, the amount is about 2 equivalents to 10 equivalents per 1 equivalent by weight of an amidine compound of Formula (II), or Formula (II-1), or a salt thereof. In yet other embodiments, the amount is about 0, 1, 2, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9, 10, 12, 15, 16, 18, 20, 30, 40, 50, 60, 70 or 80 equivalents per 1 equivalent by weight of an amidine compound of Formula (II), or Formula (II-1), or a salt thereof.

According to some embodiments of the present invention, in the method one disclosed herein, in some embodiments, each of the first organic solvent and the second organic solvent is independently a C₁₋₄ alcohol, a C₁₋₄ alcohol-water, acetone, diethyl ether, isopropyl ether, petroleum ether, tetrahydrofuran, acetonitrile, cyclopentane, cyclohexane, n-hexane, C₁₋₄ haloalkanes solvent, ethyl acetate, trifluoroethanol, 2-methoxyethanol, 1,2-dimethoxyethane, 2-methoxyethyl ether, N,N-dimethyl formamide, N-methylpyrolidone, or a combination thereof. In other embodiments, each of the first organic solvent and the second organic solvent is independently methanol, ethanol, n-propanol, i-propanol, n-butanol, tert-butanol, an ethanol-water mixture at a volume ratio from 10:90 to 90:10, an ethanol-water mixture at a volume ratio from 50:50, acetone, tetrahydrofuran, N-methylpyrolidone, trifluoroethanol, 2-methoxyethanol, 1,2-dimethoxyethane, 2-methoxyethyl ether, ethyl acetate, glycol, N,N-dimethyl formamide, or a combination thereof.

According to some embodiments of the present invention, in the method one disclosed herein, the halogenating reaction in step (B) is carried out in a third organic solvent, in some embodiments, the third organic solvent is one or more C₁₋₄ alcohols, one or more C₁₋₄ haloalkanes, acetonitrile, isopropyl ether, petroleum ether, toluene, xylene, tetrahydrofuran, ethyl acetate, acetone, or a combination thereof. In other embodiments, the third organic solvent is dichloromethane, chloroform, tetrachloromethane, acetonitrile, isopropyl ether, petroleum ether, tetrahydrofuran, methanol, ethanol, propanol, i-propanol, n-butanol, tert-butanol, ethyl acetate, acetone, or a combination thereof.

According to some embodiments of the present invention, in the method one disclosed herein, in some embodiments, the halogenating reaction in step (B) is carried out in the presence of a halogenating agent, and wherein the halogenating agent is N-bromosuccinimide, N-chlorosuccinimide, N-iodosuccinimide, 1,3-dibromo-5,5-dimethylhydantoin, or 1,3-dichloro-5,5-dimethylhydantoin, or a combination thereof.

According to some embodiments of the present invention, in the method one disclosed herein, in some embodiments, the transesterification in step (C) is performed in the present of a base, the base used is formed by reacting lithium, sodium, or potassium or a combination thereof with a C₁₋₄ alcohol.

According to some embodiments of the present invention, in the method one disclosed herein, in some embodiments, the C₁₋₄ alcohol for forming the base used in the transesterification in step (C) with lithium, sodium, or potassium, or a combination thereof is methanol, ethanol, propanol, i-propanol, n-butanol, i-butanol, or tert-butanol.

According to some embodiments of the present invention, in the method one disclosed herein, each of the lithium, sodium and potassium or a combination thereof for forming a base used in the transesterification in step (C) with a C₁₋₄ alcohol is independently applied in an amount, in some embodiments, the amount is about 0.1 equivalent to 10 equivalents per 1 equivalent by mole of a compound of Formula (VII), Formula (VII-1), or Formula (VII-2). In other embodiments, the amount is about 2 equivalents to 6 equivalents per 1 equivalent by mole of a compound of Formula (VII), Formula (VII-1), or Formula (VII-2). In still other embodiments, the amount is about 2.5 equivalents to 6 equivalents per 1 equivalent by mole of a compound of Formula (VII), Formula (VII-1), or Formula (VII-2). In yet other embodiments, the amount is about 0.1, 0.5, 1, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 9 or 10 equivalents per 1 equivalent by mole of a compound of Formula (VII), Formula (VII-1), or Formula (VII-2).

According to some embodiments of the present invention, in the method one disclosed herein, in some embodiments, the compound of Formula (IV) in step (A) is prepared by a process comprising reacting a compound of Formula (VIII) with a compound (IX),

wherein R^(3a) and R^(3b) are as defined herein.

In one aspect, provided herein is an intermediate comprising a dihydropyrimidine compound having Formula (V), or a tautomer thereof having Formula (V1), or a salt thereof, or a combination thereof,

wherein each R¹ is F; R² is Cl or Br;

R^(3b) is C₁₋₆ alkoxy, C₁₋₆ alkylamino, C₃₋₆ cycloalkoxy, C₃₋₆ cycloalkylamino, C₁₋₆alkyl-C₃₋₆-cycloalkoxy, C₆₋₁₀ arylamino, benzylamino, or benzyloxy;

R^(3a) is H or C₁₋₃ alkyl;

each R⁹ is independently H, halo, C₁₋₄ alkyl, C₁₋₄alkylthio, C₁₋₄ haloalkyl, C₃₋₆ cycloalkyl, —(CR⁷R^(7a))_(m)—C(═O)—N(R⁸R^(8a)), or —(CR⁷R^(7a))_(m)—C(═O)O—R⁸;

each R^(7a) and R⁷ is independently H, halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, —(CH₂)_(m)—OH or —(CH₂)_(m)—C(═O)O—R⁸; or R⁷ and R^(7a), together with the carbon atom to which they are attached, form a C₃₋₆ cycloalkyl group, C₂₋₉ heterocyclyl group, or —(C═O)—;

each R⁸ and R^(8a) is independently H, C₁₋₄alkyl, amino-C₁₋₄-alkyl, C₁₋₄ alkoxy, C₁₋₆alkyl-S(═O)_(q)—, C₆₋₁₀ aryl, C₁₋₉ heteroaryl, C₃₋₆ cycloalkyl, C₂₋₉ heterocyclyl, C₆₋₁₀ aryl-C₁₋₆-alkyl, C₁₋₉ heteroaryl-C₁₋₆-alkyl, C₃₋₆ cycloalkyl-C₁₋₄-alkyl, C₂₋₉ heterocyclyl-C₁₋₆-alkyl, C₂₋₉ heterocyclyl-S(═O)_(q)—, C₁₋₉ heteroaryl-S(═O)_(q)—, C₃₋₆ cycloalkyl-S(═O)_(q)—, C₆₋₁₀ aryl-S(═O)_(q)—, —(CH₂)_(m)—OH, —(CH₂)_(m)—C(═O)O—(CH₂)_(m)—H, or —(CH₂)_(m)—OC(═O)—(CH₂)_(m)—H;

each m is independently 0, 1, 2, 3, or 4;

R¹⁰ is H or deuterium;

f is 1, 2, 3, or 4;

Z is —O—, —S—, —S(═O)_(t), or —N(R⁴)—;

each of j and t is independently 0, 1, or 2; and

R⁴ is H or C₁₋₄ alkyl.

In some embodiments, provided herein is the intermediate having Formula (V-1), or a tautomer thereof having Formula (V1-1), or a salt thereof, or a combination thereof,

wherein each R^(3b) is independently C₁₋₆alkoxy, C₁₋₆alkylamino, benzyloxy, or benzylamino; R¹, R², Z and R^(3a) are as defined herein.

In some embodiments, provided herein is the intermediate having Formula (V-2), or a tautomer thereof having Formula (V1-2), or a salt thereof, or a combination thereof,

wherein R¹ is F; R² is Cl or Br;

Z is —O—, —S—, or —N(CH₃)—;

R^(3b) is methoxy, ethoxy, isopropoxy, propoxy, tert-butoxy, n-butoxy, 1-methylpropoxy, n-pentyloxy, n-hexyloxy, methylamino, ethylamino, isopropylamino, propylamino, tert-butylamino, n-butylamino, 1-methylpropylamino, n-pentylamino, n-hexylamino, benzylamino, or benzyloxy; and

R^(3a) is H, methyl, ethyl, isopropyl, or propyl.

In other aspect, provided herein is a process for preparing a dihydropyrimidine compound having Formula (I), or a tautomer thereof having Formula (Ia) (such as the method two described in scheme 2),

wherein each R¹ is F; R² is Cl or Br;

R³ is C₁₋₄ alkyl;

Z is —O—, —S—, —S(═O)_(t)—, or —N(R⁴)—;

Y is —O—, —S—, —S(═O)_(t)—, —(CH₂)_(q)—, or —N(R⁵)—;

each t and q is independently 0, 1, or 2;

each of R⁴ and R⁵ is independently H, or C₁₋₄alkyl;

each R⁶ is independently H, deuterium, halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, amino, C₁₋₄ alkylamino, C₁₋₄ alkoxy, nitro, triazolyl, tetrazyl, —(CR⁷R^(7a))_(m)—OH, —S(═O)_(q)OR^(8a), —(CR⁷R^(7a))_(m)—S(═O)_(q)N(R^(8a))₂, —(CR⁷R^(7a))_(t)—N(R^(8a))₂, —(CR⁷R^(7a))_(m)—C(═O)O—R⁸, —(CR⁷R^(7a))_(m)—C(═O)O—(CR⁷R^(7a))_(m)—OC(═O)O—R⁸, —(CR⁷R^(7a))_(m)—C(═O)O—(CR⁷R^(7a))_(m)—OC(═O)—R⁸, —(CR⁷R^(7a))_(m)—C(═O)O—(CR⁷R^(7a))_(m)—C(═O)O—R⁸, —(CR⁷R^(7a))_(m)—OC(═O)—R⁸, or —(CR⁷R^(7a))_(m)—C(═O)—N(R⁸R^(8a));

each R^(7a) and R⁷ is independently H, halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, —(CH₂)_(m)—OH, or —(CH₂)_(m)—C(═O)O—R⁸, or R^(7a) and R⁷, together with the carbon atom to which they are attached, form a C₃₋₆ cycloalkyl group, C₂₋₉ heterocyclyl group, or —(C═O)—;

each R⁸ and R^(8a) is independently H, C₁₋₄alkyl, amino-C₁₋₄-alkyl, C₁₋₄ alkoxy, C₁₋₆alkyl-S(═O)_(q)—, C₆₋₁₀ aryl, C₁₋₉ heteroaryl, C₃₋₆ cycloalkyl, C₂₋₉ heterocyclyl, C₆₋₁₀ aryl-C₁₋₆-alkyl, C₁₋₉ heteroaryl-C₁₋₆-alkyl, C₃₋₆ cycloalkyl-C₁₋₄-alkyl, C₂₋₉ heterocyclyl-C₁₋₆-alkyl, C₂₋₉ heterocyclyl-S(═O)_(q)—, C₁₋₉ heteroaryl-S(═O)_(q)—, C₃₋₆ cycloalkyl-S(═O)_(q)—, C₆₋₁₀ aryl-S(═O)_(q)—, —(CH₂)_(m)—OH, —(CH₂)_(m)—C(═O)O—(CH₂)_(m)—H, or —(CH₂)_(m)—OC(═O)—(CH₂)_(m)—H;

each R⁹ is independently H, halo, C₁₋₄ alkyl, C₁₋₄ alkylthio, C₁₋₄ haloalkyl, C₃₋₆ cycloalkyl, —(CR⁷R^(7a))_(m)—C(═O)—N(R⁸R^(8a)), or —(CR⁷R^(7a))_(m)—C(═O)O—R⁸;

R¹⁰ is H or deuterium;

n is 0, 1, 2, 3, 4, or 5;

each m is independently 0, 1, 2, 3, or 4;

f is 1, 2, 3, or 4; and

j is 0, 1, or 2;

wherein the process comprises the steps of:

step (1): reacting an amidine compound of Formula (II), or a salt thereof with an aldehyde compound of Formula (III) and a compound of Formula (IV) to obtain a compound (V) (according to some embodiments of present invention, the reaction of the step (A) may be, but not limited to an one-pot reaction),

step (2): forming a compound of Formula (X) from the compound of Formula (V) by means of a transesterification, wherein the transesterification may be carried out in the presence of a base,

wherein R^(3b) is C₁₋₆ alkoxy, C₁₋₆ alkylamino, C₃₋₆ cycloalkoxy, C₃₋₆-cycloalkylamino, C₁₋₆ alkyl-C₃₋₆-cycloalkoxy, C₆₋₁₀ arylamino, benzylamino or benzyloxy; and

R^(3a) is H or C₁₋₃ alkyl; and

step (3): halogenating the compound of Formula (X) to produce a halide; reacting the halide with a compound of Formula (VI), or a salt thereof to obtain a compound of Formula (I) or Formula (Ia).

In some embodiments, the dihydropyrimidine compound having Formula (I-1) or a tautomer thereof having Formula (Ia-1),

wherein each R⁶ is independently H, halo, C₁₋₄ alkyl, C₁₋₄haloalkyl, amino, C₁₋₄alkylamino, C₁₋₄alkoxy, nitro, triazolyl, tetrazyl, —(CR⁷R^(7a))_(m)—OH, —S(═O)OR^(8a), —(CR⁷R^(7a))_(m)—S(═O)_(q)N(R^(8a))₂, —(CR⁷R^(7a))_(t)—N(R^(8a))₂, —(CR⁷R^(7a))_(m)—C(═O)O—R⁸, —(CR⁷R^(7a))_(m)—C(═O)O—(CR⁷R^(7a))_(m)—OC(═O)O—R⁸, —(CR⁷R^(7a))_(m)—C(═O)O—(CR⁷R^(7a))_(m)—OC(═O)—R⁸, —(CR⁷R^(7a))_(m)—C(═O)O—(CR⁷R^(7a))_(m)—C(═O)O—R⁸, —(CR⁷R^(7a))_(m)—OC(═O)—R⁸, or —(CR⁷R^(7a))_(m)—C(═O)—N(R⁸R^(8a)); and

each R^(7a) and R⁷ is independently H, C₁₋₄alkyl, C₁₋₄ haloalkyl, —(CH₂)_(m)—OH, or —(CH₂)_(m)—C(═O)O—R⁸;

R¹, R², R³, Z, n, Y, m, q, R^(8a), t and R⁸ are as defined herein;

According to some embodiments of the present invention, the method two for preparing the dihydropyrimidine compound having Formula (I-1), or a tautomer thereof having Formula (Ia-1) comprises the steps of:

step (1) reacting an amidine compound of Formula (II-1), or a salt thereof with an aldehyde compound of Formula (III-1) and the compound of Formula (IV) to obtain a compound (V-1) (according to some embodiments of present invention, the reaction of the step (A) may be, but not limited to an one-pot reaction).

step (2): forming a compound of Formula (X-1) from the compound of Formula (V-1) by means of a transesterification, wherein the transesterification may be carried out in the presence of a base,

wherein R^(3b) is C₁₋₆ alkoxy, C₁₋₆alkylamino, benzylamino or benzyloxy; R^(3a) is as defined herein; and

step (3): halogenating the compound of Formula (X-1) to form a halide; and then reacting the halide with a compound of Formula (VI), or a salt thereof to obtain a compound of Formula (I-1) or Formula (Ia-1).

In other embodiments, the dihydropyrimidine compound having Formula (I-2), or a tautomer thereof having Formula (Ia-2)

wherein R¹ is F; and R² is Cl or Br; R³, Z, n, Y and R⁶ are as defined herein.

According to embodiments of present invention, the method two for preparing the dihydropyrimidine compound having Formula (I-2), or a tautomer thereof having Formula (Ia-2) comprises the steps of:

step (1): reacting an amidine compound of Formula (II-1), or a salt thereof with an aldehyde compound of Formula (III-2) and the compound of Formula (IV) to obtain a compound (V-2) (according to some embodiments of the present invention, the reaction of the step (A) may be an one-pot reaction),

step (2): forming a compound of Formula (X-2) from the compound of Formula (V-2) by means of a transesterification, wherein the transesterification may be carried out in the presence of a base,

wherein R^(3b) and R^(3a) are as defined herein; and

step (3): halogenating the compound of Formula (X-2) to produce a halide; reacting the halide with a compound of Formula (VI), or a salt thereof to obtain a compound of Formula (I-2) or Formula (Ia-2).

According to some embodiments of the present invention, in the method two disclosed herein, in some embodiments, R³ is methyl, ethyl, propyl, isopropyl, tert-butyl, or butyl; Z is —O—, —S—, or —N(CH₃)—; Y is —O—, —S—, —S(═O)₂, or —(CH₂)_(q)—; each R⁶ is independently H, halo, C₁₋₄alkyl, C₁₋₄haloalkyl, amino, C₁₋₄alkylamino, C₁₋₄alkoxy, nitro, triazolyl, tetrazyl, —(CR⁷R^(7a))_(m)—OH, —(CR⁷R^(7a))_(m)—C(═O)O—R⁸, —(CR⁷R^(7a))_(t)—N(R^(8a))₂, —S(═O)_(q)OR^(8a), —(CR⁷R^(7a))_(m)—S(═O)N(R^(8a))₂, —(CR⁷R^(7a))_(m)—C(═O)O—(CR⁷R^(7a))_(m)—OC(═O)O—R⁸, —(CR⁷R^(7a))_(m)—C(═O)O—(CR⁷R^(7a))_(m)—OC(═O)—R⁸, —(CR⁷R^(7a))_(m)—C(═O)O—(CR⁷R^(7a))_(m)—C(═O)O—R⁸, —(CR⁷R^(7a))_(m)—OC(═O)—R⁸, or —(CR⁷R^(7a))_(m)—C(═O)N(R⁸R^(8a)); each R^(7a) and R⁷ is independently H, methyl, ethyl, trifluoromethyl, —(CH₂)_(m)—OH, or —(CH₂)_(m)—C(═O)O—R⁸; each R⁸ and R^(8a) is independently H, methyl, ethyl, propyl, isopropyl, aminomethyl, methoxy, C₁₋₄alkyl-S(═O)₂—, phenyl, pyridyl, thiazolyl, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyrimidinyl, pyridazinyl, diazolyl, triazolyl, tetrazolyl, thienyl, pyrazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyrazinyl, pyranyl, triazinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyl-S(═O)₂—, cyclobutyl-S(═O)₂—, cyclopentyl-S(═O)₂—, cyclohexyl-S(═O)₂—, naphthyl-S(═O)₂—, phenyl-S(═O)₂—, —(CH₂)_(m)—OH, —(CH₂)_(m)—C(═O)O—(CH₂)_(m)—H or —(CH₂)_(m)—OC(═O)—(CH₂)_(m)—H; R^(3b) is methoxy, ethoxy, isopropoxy, propoxy, tert-butoxy, n-butoxy, 1-methylpropoxy, n-pentyloxy, n-hexyloxy, methylamino, ethylamino, isopropylamino, propylamino, tert-butylamino, n-butylamino, 1-methylpropylamino, n-pentylamino, n-hexylamino, benzylamino or benzyloxy; and R^(3a) is H, methyl, ethyl, isopropyl, or propyl.

According to some embodiments of the present invention, in the method two disclosed herein, the reaction in step (1) is performed at a temperature from 25° C. to 154° C. In some other embodiments, the reaction in step (1) is performed at a temperature from 60° C. to 100° C.

According to some embodiments of the present invention, in the method two disclosed herein, the step (1) further comprises the step of cooling the resulting compound (V) of step (1) to obtain a solid compound (V) at a cooling temperature from −40° C. to 40° C. In other embodiments, the cooling temperature is from 25° C. to 40° C. In some embodiments, the cooling is performed for a period of from 0 hour to 24 hours. In some other embodiments, the cooling is performed for from 1 minute to 24 hours. In still other embodiments, t the cooling is performed for from 1 hour to 8 hours.

According to some embodiments of the present invention, in the method two disclosed herein, the amidine compound of Formula (II) reacts with the aldehyde compound of Formula (III) and the compound of Formula (IV) in a first organic solvent. In some embodiments, the first organic solvent is applied in an amount of 0 equivalent to 80 equivalents per 1 equivalent by weight of the amidine compound of Formula (II), or a salt thereof. In some other embodiments, the first organic solvent is applied in an amount of 1 equivalent to 20 equivalents per 1 equivalent by weight of the amidine compound of Formula (II), or a salt thereof.

According to some embodiments of the present invention, in the method two disclosed herein, step (1) further comprises the step of purifying the solid compound (V). In some embodiments, the solid compound of Formula (V) is purified by at least one of the following methods: (1) trituration; (2) recrystallization; (3) washing.

According to some embodiments of the present invention, the purification is carried out in a second organic solvent. In some embodiments, the second organic solvent is applied in an amount of 2 equivalent to 20 equivalents per 1 equivalent by weight of the amidine compound of Formula (II), or a salt thereof.

According to some embodiments of the present invention, in the method two disclosed herein, the trituration is carried out at a temperature from −20° C. to 50° C. In some embodiments, the trituration is carried out at a temperature from 5° C. to 40° C.

According to some embodiments of the present invention, in the method two disclosed herein, the recrystallization comprises a crystallization process at a temperature from −30° C. to 40° C. In some embodiments, the crystallization process is carried out at a temperature from 0° C. to 40° C. In some embodiments, the recrystallization comprises a crystallization process of from 1 hour to 20 hours. In some other embodiments, the recrystallization comprises a crystallization process of from 1 hour to 12 hours.

According to embodiments of present invention, in the method two disclosed herein, the washing is performed at a temperature from 0° C. to 30° C.

According to some embodiments of the present invention, in the method two disclosed herein, in some embodiments, each of the first organic solvent and the second organic solvent is independently a C₁₋₄ alcohol, a C₁₋₄ alcohol-water, acetone, diethyl ether, isopropyl ether, petroleum ether, tetrahydrofuran, acetonitrile, cyclopentane, cyclohexane, n-hexane, C₁₋₄ haloalkanes solvent, ethyl acetate, trifluoroethanol, 2-methoxyethanol, 1,2-dimethoxyethane, 2-methoxyethyl ether, N,N-dimethyl formamide, N-methylpyrolidone, or a combination thereof. In some other embodiments, each of the first organic solvent and the second organic solvent is independently methanol, ethanol, n-propanol, i-propanol, n-butanol, tert-butanol, an ethanol-water mixture at a volume ratio from 10:90 to 90:10, an ethanol-water mixture at a volume ratio from 50:50, acetone, tetrahydrofuran, N-methylpyrolidone, trifluoroethanol, 2-methoxyethanol, 1,2-dimethoxyethane, 2-methoxyethyl ether, ethyl acetate, glycol, N,N-dimethyl formamide, or a combination thereof.

According to some embodiments of the present invention, in the method two disclosed herein, in some embodiments, the transesterification in step (2) is performed in the present of a base, and wherein the base is formed by reacting lithium, sodium, or potassium, or a combination thereof with a C₁₋₄ alcohol.

According to some embodiments of the present invention, in the method two disclosed herein, in some embodiments, the C₁₋₄ alcohol for forming the base used in the transesterification in step (2) with lithium, sodium, or potassium, or a combination thereof is methanol, ethanol, propanol, i-propanol, n-butanol, i-butanol, or tert-butanol.

According to some embodiments of the present invention, in the method two disclosed herein, each of the lithium, sodium and potassium, or a combination thereof for forming a base used in the transesterification in step (2) with a C₁₋₄ alcohol is independently applied in an amount, in some embodiments, the amount is about 0.5 l equivalent to 10 equivalents per 1 equivalent by mole of a compound of Formula (V), Formula (V-1), or Formula (V-2). In other embodiments, the amount is about 2 equivalents to 8 equivalents per 1 equivalent by mole of a compound of Formula (V), Formula (V-1), or Formula (V-2). In still other embodiments, the amount is about 2.5 equivalents to 8 equivalents per 1 equivalent by mole of a compound of Formula (V), Formula (V-1), or Formula (V-2). In yet other embodiments, the amount is about 0.5, 1, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 9 or 10 equivalents per 1 equivalent by mole of a compound of Formula (V), Formula (V-1), or Formula (V-2).

According to some embodiments of the present invention, in the method two disclosed herein, the halogenating reaction in step (3) is carried out in a forth organic solvent, in some embodiments, the forth organic solvent is one or more C₁₋₄ alcohols, one or more C₁₋₄ haloalkanes, acetonitrile, isopropyl ether, petroleum ether, toluene, xylene, tetrahydrofuran, ethyl acetate, acetone, or a combination thereof. In other embodiments, the forth organic solvent is dichloromethane, chloroform, tetrachloromethane, acetonitrile, isopropyl ether, petroleum ether, tetrahydrofuran, methanol, ethanol, propanol, i-propanol, n-butanol, tert-butanol, ethyl acetate, acetone, or a combination thereof.

According to some embodiments of the present invention, in the method two disclosed herein, in some embodiments, the halogenating reaction in step (3) is carried out in the presence of a halogenate agent, and wherein the halogenate agent is N-bromosuccinimide, N-chlorosuccinimide, N-iodosuccinimide, 1,3-dibromo-5,5-dimethylhydantoin, or 1,3-dichloro-5,5-dimethylhydantoin, or a combination thereof

DEFINITIONS AND GENERAL TERMINOLOGY

The term “alkyl” or “alk-” or “alkyl group” as used interchangeably in the context of the present invention, such as in alkyl, aminoalkyl, alkylamino, alkylthio or alkoxy, relfers to a saturated linear or branched-chain monovalent hydrocarbon radical of 1 to 10 carbon atoms. Wherein, the alkyl group may be optionally substituted with one or more substituents disclosed herein. In some embodiments, the alkyl group contains 1-10 carbon atoms. In other embodiments, the alkyl group contains 1-6 carbon atoms. In other embodiments, the alkyl group contains 1-4 carbon atoms. In still other embodiments, the alkyl group contains 1-3 carbon atoms.

Some non-limiting examples of the alkyl group include, methyl (Me, —CH₃), ethyl (Et, —CH₂CH₃), n-propyl (n-Pr, —CH₂CH₂CH₃), isopropyl (i-Pr, —CH(CH₃)₂), n-butyl (n-Bu, —CH₂CH₂CH₂CH₃), isobutyl (i-Bu, —CH₂CH(CH₃)₂), sec-butyl (s-Bu, —CH(CH₃)CH₂CH₃), tert-butyl (t-Bu, —C(CH₃)₃), n-pentyl (—CH₂CH₂CH₂CH₂CH₃), 2-pentyl (—CH(CH₃)CH₂CH₂CH₃), 3-pentyl (—CH(CH₂CH₃)₂), 2-methyl-2-butyl (—C(CH₃)₂CH₂CH₃), 3-methyl-2-butyl (—CH(CH₃)CH(CH₃)₂), 3-methyl-1-butyl (—CH₂CH₂CH(CH₃)₂), 2-methyl-1-butyl (—CH₂CH(CH₃)CH₂CH₃), n-hexyl (—CH₂CH₂CH₂CH₂CH₂CH₃), 2-hexyl (—CH(CH₃)CH₂CH₂CH₂CH₃), 3-hexyl (—CH(CH₂CH₃)(CH₂CH₂CH₃)), 2-methyl-2-pentyl (—C(CH₃)₂CH₂CH₂CH₃), 3-methyl-2-pentyl (—CH(CH₃)CH(CH₃)CH₂CH₃), 4-methyl-2-pentyl (—CH(CH₃)CH₂CH(CH₃)₂), 3-methyl-3-pentyl (—C(CH₃)(CH₂CH₃)₂), 2-methyl-3-pentyl (—CH(CH₂CH₃)CH(CH₃)₂), 2,3-dimethyl-2-butyl (—C(CH₃)₂CH(CH₃)₂), 3,3-dimethyl-2-butyl (—CH(CH₃)C(CH₃)₃, n-heptyl and n-octyl, etc.

The term “aminoalkyl” refers to a C₁₋₁₀ linear or branched-chain alkyl group substituted with one or more amino groups. In some embodiments, the aminoalkyl group refers to a C₁₋₆ aminoalkyl group, wherein the alkyl group is as defined herein. Some non-limiting examples of the aminoalkyl group include aminomethyl, 2-aminoethyl, 2-aminoisopropyl, aminopropyl, aminobutyl and aminohexyl, etc.

The term “alkoxy” refers to an alkyl group attached to the rest part of the molecule through an oxygen atom, wherein the alkyl group is as defined herein. Unless otherwise specified, the alkoxy group contains 1-10 carbon atoms. In some embodiments, the alkoxy group contains 1-6 carbon atoms. In other embodiments, the alkoxy group contains 1-4 carbon atoms. In still other embodiments, the alkoxy group contains 1-3 carbon atoms. Some non-limiting examples of the alkoxy group include methoxy (MeO, —OCH₃), ethoxy (EtO, —OCH₂CH₃), propoxy (n-PrO, n-propoxy, —OCH₂CH₂CH₃), isopropoxy (i-PrO, i-propoxy, —OCH(CH₃)₂), n-butoxy (n-BuO, —OCH₂CH₂CH₂CH₃), 1-methyl-propoxy (s-BuO, s-butoxy, —OCH(CH₃)CH₂CH₃), 2-methyl-1-propoxy (i-BuO, i-butoxy, —OCH₂CH(CH₃)₂), tert-butoxy (t-BuO, t-butoxy, —OC(CH₃)₃), n-pentoxy (—OCH₂CH₂CH₂CH₂CH₃), 2-pentoxy (—OCH(CH₃)CH₂CH₂CH₃), 3-pentoxy (—OCH(CH₂CH₃)₂), 2-methyl-2-butoxy (—OC(CH₃)₂CH₂CH₃), 3-methyl-2-butoxy (—OCH(CH₃)CH(CH₃)₂), 3-methyl-1-butoxy (—OCH₂CH₂CH(CH₃)₂), 2-methyl-1-butoxy (—OCH₂CH(CH₃)CH₂CH₃) and n-hexyloxy (—OCH₂CH₂CH₂CH₂CH₂CH₃), etc.

The terms “haloalkyl”, “haloalkenyl” or “haloalkoxy” refer to alkyl, alkenyl or alkoxy, as the case may be, substituted with one or more halogen atoms. Wherein the alkyl, alkenyl and alkoxy are as defined herein. Some non-limiting examples of these groups include —CF₃, —CH₂Cl, —CH₂CF₃, —CH₂CH₂CF₃, —OCF₃, —OCHF₂, —OCHCl₂, —OCH₂CHF₂, —OCH₂CHCl₂ and —OCH(CH₃)CHF₂, etc.

The term “alkylamino” refers to “N-alkylamino” and “N,N-dialkylamino” wherein amino groups are independently substituted with one alkyl radical or two alkyl radicals, respectively. Wherein the alkyl group and amino group are as defined herein. In some embodiments, the alkylamino radical is “lower alkylamino” radical having one or two C₁₋₆alkyl groups attached to a nitrogen atom. In other embodiments, the alkylamino radical refers to C₁₋₄ lower alkylamino group. In still other embodiments, the alkylamino radical refers to C₁₋₃ lower alkylamino group. Some non-limiting examples of suitable alkylamino radical include mono or dialkylamino. Some examples include, but are not limited to, methylamino, ethylamino, isopropylamino, propylamino, tert-butylamino, n-butylamino, 1-methylpropylamino, n-pentylamino, n-hexylamino, N,N-dimethylamino and N,N-diethylamino, etc.

The term “alkylthio” refers to a radical containing a linear or branched-alkyl radical of one to ten carbon atoms, attached to a divalent sulfur atom. Wherein the alkyl group is as defined herein. Some non-limiting examples of the alkylthio group include methylthio (CH₃S—) and ethylthio, etc.

The term “cycloalkyl” refers to a monovalent or multivalent saturated ring having 3 to 12 carbon atoms as a monocyclic, bicyclic, or tricyclic ring system. The cycloalkyl group may be optionally substituted with one or more substituents disclosed herein. In some embodiments, the cycloalkyl contains 3 to 12 carbon atoms. In still other embodiments, the cycloalkyl contains 3 to 8 carbon atoms. In yet other embodiments, the cycloalkyl contains 3 to 6 carbon atoms. Some examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cyclohendecyl and cyclododecyl, etc.

The term “cycloalkylalkyl” refers to an alkyl radical substituted with one or more cycloalkyl radicals, wherein the cycloalkyl and alkyl are as defined herein. Some non-limiting examples of the cycloalkylalkyl group include cyclopropylmethyl, cyclopropylethyl, cyclopropylpropyl, cyclobutylmethyl, cyclobutylethyl, cyclobutylpropyl, cyclopentylmethyl, cyclopentylethyl, cyclopentylpropyl, cyclohexylmethyl, cyclohexylethyl and cyclohexylpropyl, etc.

The term “cycloalkyloxy” refers to a cycloalkyl group, attached to the rest part of the molecule through an oxygen atom. Wherein the cycloalkyl group is as defined herein. Some non-limiting examples of the cycloalkyloxy group include cyclopropoxy, cyclopentyloxy and cyclohexyloxy, etc.

The term “cycloalkylamino” refers to an amino group is substituted with one or two cycloalkyl radicals. Some non-limiting examples of such radical include cyclopropylamino, cyclobutylamino, cyclopentylamino and cyclohexylamino, etc. In some embodiments, the cycloalkyl of cycloalkylamino group may be optionally substituted with one or more substituents disclosed herein.

The term “heterocyclyl” refers to a saturated or unsaturated, nonaromatic, monocyclic, bicyclic or tricyclic ring system in which at least one ring member is selected from nitrogen, sulfur and oxygen. Wherein, the heterocyclyl group may be optionally substituted with one or more substituents disclosed herein. Unless otherwise specified, the heterocyclyl group may be carbon or nitrogen linked, and a —CH₂— group can be optionally replaced by a —C(═O)— group. In which, the sulfur can be optionally oxygenized to S-oxide and the nitrogen can be optionally oxygenized to N-oxide. In some embodiments, the heterocyclyl group may be a C₂₋₁₀ heterocyclyl group, which refers to a heterocyclyl group containing 2 to 10 carbon atoms and at least one heteroatom selected from nitrogen, sulfur and oxygen. In other embodiments, the heterocyclyl group may be a C₂₋₉ heterocyclyl group, which refers to a heterocyclyl group containing 2 to 9 carbon atoms and at least one heteroatom selected from nitrogen, sulfur and oxygen. In still other embodiments, the heterocyclyl group may be a C₂₋₇ heterocyclyl group, which refers to an heterocyclyl group containing 2 to 7 carbon atoms and at least one heteroatom selected from nitrogen, sulfur and oxygen. In yet other embodiments, the heterocyclyl group may be a C₂₋₅ heterocyclyl group, which refers to a heterocyclyl group containing 2 to 5 carbon atoms and at least one heteroatom selected from nitrogen, sulfur and oxygen. Some non-limiting examples of the heterocyclyl group include oxiranyl, thietanyl, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, oxazolidinyl, tetrahydrofuranyl, dihydrothienyl, dihydropyranyl, piperidinyl, morpholinyl, tetrahydropyrimidinyl, oxazinanyl, thiomorpholinyl and piperazinyl, etc. A —CH₂— group of the heterocyclyl group may be substituted with —C(═O), some non-limiting examples of such group include 2-oxopyrrolidinyl, 2-piperidinonyl, 3-morpholinonyl, 3-thiomorpholinonyl and oxotetrahydropyrimidinyl, etc.

The term “heterocyclylalkyl” refers to a heterocyclyl group attached to the rest of the molecule through an alkyl group, wherein the heterocyclyl and alkyl are as defined herein. Some non-limiting examples of such group include pyrrolidinylmethyl, piperidinylmethyl, piperidinylethyl, morpholinylmethyl and morpholinylethyl, etc.

The term “halogen” refers to fluorine(F), chlorine(Cl), bromine(Br) or iodine(I).

The term “aryl” refers to monocyclic, bicyclic and tricyclic carbocyclic ring systems having a total of six to fourteen ring members, or six to twelve ring members, or six to ten ring members, wherein at least one ring in the system is aromatic, wherein each ring in the system contains 3 to 7 ring members and that has a single point or multipoint of attachment to the rest of the molecule. Wherein the aryl may be optionally substituted with one or more substituents disclosed herein. The term “aryl” and “aromatic ring” can be used interchangeably herein. Some non-limiting examples of the aryl group include phenyl, 2,3-dihydro-1H-indenyl, naphthalenyl and anthracenyl, etc.

The term “arylalkyl” or “aralkyl” refers to an aryl group attached to the rest of the molecule through an alkyl group, wherein the aryl and alkyl are as defined herein. Some non-limiting examples of such group include benzyl, phenylethyl and naphthalenylmethyl, etc.

The term “arylamino” refers to an amino group substituted with one or two aryl groups. Some non-limiting examples of such group included N-phenylamino. In some embodiments, the aryl group of the arylamino may be further substituted.

The term “heteroaryl” refers to monocyclic, bicyclic and tricyclic carbocyclic ring systems having a total of five to twelve ring members, or five to ten ring members, or five to six ring members, wherein at least one ring in the system is aromatic, and in which at least one ring member is selected from nitrogen, sulfur and oxygen, and wherein each ring in the system contains 5 to 7 ring members and that has a single point or multipoint of attachment to the rest of the molecule. The term “hetreroaryl” and “heteroaromatic ring” or “heteroaromatic compound” can be used interchangeably herein. In other embodiments, the heteroaryl group may be a C₁₋₉ heteroaryl group, which refers to a heteroaryl group containing 1 to 9 carbon atoms and at least one heteroatom selected from nitrogen, sulfur and oxygen. In other embodiments, the heteroaryl group may be a C₁₋₇ heteroaryl group, which refers to a heteroaryl group containing 1 to 7 carbon atoms and at least one heteroatom selected from nitrogen, sulfur and oxygen. In still other embodiments, the heteroaryl group may be a C₁₋₆ heteroaryl group, which refers to a heteroaryl group containing 1 to 6 carbon atoms and at least one heteroatom selected from nitrogen, sulfur and oxygen. In other embodiments, the heteroaryl group may be a C₁₋₅ heteroaryl group, which refers to a heteroaryl group containing 1 to 5 carbon atoms and at least one heteroatom selected from nitrogen, sulfur and oxygen. In still other embodiments, the heteroaryl group may be a C₁₋₄ heteroaryl group, which refers to a heteroaryl group containing 1 to 4 carbon atoms and at least one heteroatom selected from nitrogen, sulfur and oxygen. In yet other embodiments, the heteroaryl group may be a C₁₋₃ heteroaryl group, which refers to a heteroaryl group containing 1 to 3 carbon atoms and at least one heteroatom selected from nitrogen, sulfur and oxygen. Some non-limiting examples of the heteroaryl group include furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, thienyl, diazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyranyl and triazinyl, etc, and also include, but are not limited to the following bicycle ring: benzimidazolyl, benzofuranyl, benzothiophenyl, indolyl, oxoindolyl, indolinyl, imidazopyridyl, pyrazopryridyl, pyrazopyrimidinyl, quinolyl, isoquinolyl and quinazolinyl, etc. The heteroaryl group may be optionally substituted with one or more substituents disclosed herein.

The term “heteroarylalkyl” refers to an heteroaryl group attached to the rest of the molecule through a alkyl group, wherein the heteroaryl and alkyl are as defined herein. The “heteroarylalkyl” group may be optionally substituted with one or more substituents disclosed herein. Some non-limiting examples of such group included pyridylmethyl, pyrrolylethyl and quinolylmethyl, etc.

The term “comprise” is an open expression, it means comprising the contents disclosed herein, but don't exclude other contents.

Furthermore, unless otherwise stated, the phrase “each . . . is independently” is used interchangeably with the phrase “each (of) . . . and . . . is independently”. It should be understood broadly that the specific options expressed by the same symbol are independently of each other in different radicals; or the specific options expressed by the same symbol are independently of each other in same radicals. Such as Formula (a), multiple n are independently of each other, multiple R⁶ are independently of each other,

As described herein, a system containing a group formed by a double bond connect with a wave bond indicates that it is (Z) or (E) configuration, or a combination thereof.

The solvent used for the reaction of the invention is not particularly restricted, any solvent is contained in the invention so long as it can dissolve the raw materials to a certain extent and don't inhibit the reaction. Additionally, many similar modifications in the art, substitutions to same object, or solvent, solvent composition and the solvent composition with different proportions which are equivalent to those described in the invention, all are deemed to be included in the present invention. Wherein the solvent could be alcohols, alcohol-water mixtures, ethers, halohydrocarbons, esters, ketones, aromatic hydrocarbons, alkanes, acetonitrile, trifluoroethanol, N,N-dimethyl formamide (DMF), N-methylpyrolidone (NMP), or a combination thereof. Such as methanol, ethanol, n-propanol, i-propanol, n-butanol, i-butanol, a ethanol-water mixture at a volume ratio 50:50, trifluoroethanol, tert-butanol, petroleum ether, n-pentane, n-hexane, n-heptane, cyclohexane, isopropyl ether, DMF, tetrahydrofuran, ethyl ether, dioxane, methyl tertiary butyl ether (MTBE), 1,2-dimethoxylethane, NMP, 2-methoxyethanol, 1,2-dimethoxyethane, diethylene glycol dimethyl ether, triethylene glycol dimethyl ether, dichloromethane, 1,2-dichloroethane, chloroform, tetrachloromethane, ethyl acetate, isopropyl acetate, acetone, butanone, benzene, toluene, xylene or a combination thereof.

The amount of water in the solvent is not particularly restricted. So long as the solvent containing a certain amount of water can be used in the reaction disclosed herein, which is deemed to be included in the present invention. The amount of water in the solvent is approximately less than 0.05%, less than 0.1%, less than 0.2%, less than 0.5%, less than 5%, less than 10%, less than 25%, less than 30%, or 0%.

The solvent used for the recrystallization of the invention is not particularly restricted, any solvent is contained in the invention so long as it can dissolve the crude product and the crystal product can precipitate out under certain conditions. Additionally, many similar modifications in the art, substitutions to same object, or solvent, solvent composition and the solvent composition with different proportions which are equivalent to those described in the invention, all are deemed to be included in the present invention. Wherein the solvent could be alcohols, alcohol-water mixtures, ethers, alkanes, halohydrocarbons, esters, ketones, aromatic hydrocarbons, acetonitrile, N,N-dimethyl formamide (DMF), N-methylpyrolidone (NMP), or a combination thereof. Such as methanol, ethanol, n-propanol, i-propanol, n-butanol, i-butanol, tert-butanol, trifluoroethanol, ethanol-water mixture at a volume ratio 50:50, petroleum ether, n-pentane, n-hexane, n-heptane, cyclohexane, DMF, tetrahydrofuran, ethyl ether, isopropyl ether, dioxane, methyl tertiary butyl ether (MTBE), 1,2-dimethoxylethane, NMP, 2-methoxyethanol, 1,2-dimethoxyethane, diethylene glycol dimethyl ether, triethylene glycol dimethyl ether, dichloromethane, 1,2-dichloroethane, chloroform, tetrachloromethane, ethyl acetate, isopropyl acetate, acetone, butanone, benzene, toluene, xylene or a combination thereof.

Any temperature is included in the present invention so long as it is applicable for the one-pot reaction. Additionally, many similar modifications in the art, substitutions to same object, or temperature and temperature scope which are equivalent to those described in the invention, all are deemed to be included in the present invention. In some embodiments, the one-pot reaction temperature is from approximately room temperature (usually 25° C.) to 154° C. The reaction is carried out at a low temperature at the beginning or at the earlier stage, after rising of the temperature, the reaction is carried out at a higher temperature, which may be from approximately 25° C. to solvent boiling point, from approximately 30° C. to solvent boiling point, from approximately 25° C. to 154° C., from approximately 30° C. to 154° C.

Any temperature is included in the present invention so long as it is applicable for the cooling after one-pot reaction. Additionally, many similar modifications in the art, substitutions to same object, or temperature and temperature scope which are equivalent to those described in the invention, all are deemed to be included in the present invention. In some embodiments, the cooling temperature is approximately from −80° C. to 60° C. After the one-pot reaction is complete, the reaction mixture cooling is carried out at a higher temperature, may be from solvent boiling point to 60° C., from solvent boiling point to 40° C., from solvent boiling point to 30° C., from solvent boiling point to 25° C., from solvent boiling point to 0° C., from solvent boiling point to −10° C., from solvent boiling point to −15° C., from solvent boiling point to −20° C., from solvent boiling point to −40° C., from solvent boiling point to −50° C., or from solvent boiling point to −80° C., and may be from approximately 60° C. to −20° C., from approximately 50° C. to −20° C., from approximately 40° C. to 10° C., from approximately 30° C. to 10° C., or from approximately room temperature (usually 25° C.) to 10° C. The reaction mixture cooling at the later stage is carried out at a lower temperature, may be from approximately −80° C. to approximately 10° C., from approximately −60° C. to approximately 10° C., from approximately −40° C. to approximately 10° C., from approximately −20° C. to approximately 10° C., from approximately −10° C. to approximately 10° C., from approximately 0° C. to approximately 10° C.

Any temperature is included in the present invention so long as it can applicable for the crystallization process of recrystallization. Additionally, many similar modifications in the art, substitutions to same object, or temperature and temperature scope which are equivalent to those described in the invention, all are deemed to be included in the present invention. In some embodiments, the crystallization temperature is from approximately −80° C. to 60° C. After all the crude product is dissolved completely, the crystallization is at a higher temperature, may be from solvent boiling point to 60° C., from solvent boiling point to 50° C., from solvent boiling point to 40° C., from solvent boiling point to 30° C., from solvent boiling point to 25° C., from solvent boiling point to 0° C., from solvent boiling point to −10° C., from solvent boiling point to −15° C., from solvent boiling point to −20° C., from solvent boiling point to −30° C., from solvent boiling point to −40° C., from solvent boiling point to −50° C., or solvent boiling point to −80° C., and may be from approximately 60° C. to −20° C., from approximately 50° C. to −20° C., from approximately 40° C. to 10° C., from approximately 30° C. to 10° C., or from approximately room temperature (usually 25° C.) to 10° C. The crystallization at the later stage is at a lower temperature, may be from approximately −80° C. to approximately 10° C., from approximately −60° C. to approximately 10° C., from approximately −40° C. to approximately 10° C., from approximately −20° C. to approximately 10° C., from approximately −10° C. to approximately 10° C., from approximately 0° C. to approximately 10° C.

Any halogenating agent is included in the present invention so long as it is applicable for the halogenating reaction. For example, N-bromosuccinimide (NBS), N-chlorosuccinimide (NCS), N-iodosuccinimide (NIS), 1,3-dibromo-5,5-dimethylhydantoin, 1,3-dichloro-5,5-dimethylhydantoin, iodomethane, etc.

The base used in the present invention may be an organic base or inorganic base. The organic base may be triethylamine, trimethylamine, N,N-diisopropylethylamine, N-methylmorpholine, N-methylpiperidine or a combination thereof; and can also be a base formed by reacting an organic solvent with an alkali metal. The alkali metal comprises lithium, sodium and potassium. The organic solvent can be one or more alcohols, or a combination thereof. The alcohols include, but are not limited to, methanol, ethanol, propanol, i-propanol, n-butanol, i-butanol, tert-butanol and a combination thereof. The inorganic bases include, but are not limited to, alkali metal hydroxide, alkaline earth metal hydroxide, alkali metal alkoxide, alkaline earth metal alkoxide, alkali metal carbonate, alkaline earth metal carbonate and ammonia. In some embodiments, the inorganic base is ammonia, sodium hydroxide, calcium hydroxide, magnesium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, sodium tert-butoxide, sodium isopropoxide or potassium tert-butoxide.

After the reaction proceeds to a certain extent in the present invention, such as the raw material is consumed more than 20%, more than 30%, more than 40%, more than 50%, more than 70%, more than 80%, more than 90%, more than 95%, or completely by monitoring, the reaction mixture is worked up, such as cooled, collected, drawn, filtered, separated, purified or a combination thereof. The reaction can be monitored by conventional method such as thin-layer chromatography (TLC), high performance liquid chromatography (HPLC), gas chromatography (GC), and the like. The reaction mixture can be worked up by conventional method, for example, the crude product can be collected by concentrating the reaction mixture through vacuum evaporation or conventional distillation and used directly in the next operation; or the crude product can be obtained by filtration of the reaction mixture and used directly in the next operation; or the crude product can be get by pouring out the supernatant liquid of the reaction mixture after standing a while and used directly in the next operation; and the reaction mixture can be purified by suitable methods such as extraction, distillation, crystallization, column chromatography, washing, trituration with suitable organic solvents or a combination thereof.

Unless otherwise stated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric) forms of the structure; for example, the R and S configurations for each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, or geometric mixtures of the present compounds are within the scope disclosed herein.

Stereochemical definitions and conventions used herein generally follow Parker et al., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York and Eliel et al., Stereochemistry of Organic Compounds, John Wiley & Sons, Inc., New York, 1994. The compounds disclosed herein may contain asymmetric or chiral centers, and therefore exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds disclosed herein, including, but not limited to, diastereomers, enantiomers and atropisomers, as well as mixtures thereof such as racemic mixtures, form part of the present invention. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. In describing an optically active compound, the prefixes D and L, or R and S, are used to denote the absolute configuration of the molecule about its chiral center(s). The prefixes d and 1 or (+) and (−) are employed to designate the sign of rotation of plane-polarized light by the compound, with (−) or 1 meaning that the compound is levorotatory. A compound prefixed with (+) or d is dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of one another. A specific stereoisomer is referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture. A 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which may occur where there has been no stereoselection or stereospecificity in a chemical reaction or process. The term “racemic mixture” or “racemate” refers to an equimolar mixture of two enantiomeric species, devoid of optical activity.

The term “tautomer” or “tautomeric form” refers to structural isomers of different energies which are interconvertible via a low energy barrier. If tautomerism could happen (such as in a solvent), the chemical balance between tautomers can be reached. For example, proton tautomers (also known as prototropic tautomers) include interconversions via migration of a proton, such as keto-enol and imine-enamine isomerizations. Valence tautomers include interconversions by reorganization of some of the bonding electrons. The specific example of keto-enol tautomerisms is hexane-2,4-dione and 4-hydroxyhex-3-en-2-one tautomerism. Another example of tautomerisms is phenol-keto tautomerism. The specific example of phenol-keto tautomerisms is pyridin-4-ol and pyridin-4(3H)-one tautomerism. Unless otherwise stated, all tautomers of the present compounds within the scope disclosed herein.

General Experimental Procedures

In the present invention, if the chemical name of the compound doesn't match the corresponding structure, the compound is characterized by the corresponding structure.

Generally, the compounds of Formula (I), Formula (Ia), Formula (I-1), Formula (Ia-1), Formula (I-2) or Formula (Ia-2) disclosed herein may be prepared by methods described herein, wherein the substituents are as defined in Formula (I), Formula (Ia), Formula (I-1), Formula (Ia-1), Formula (I-2) or Formula (Ia-2), except where further noted. The following examples are presented to further exemplify the invention.

Persons skilled in the art will recognize that the chemical reactions described may be readily adapted to prepare a number of other compounds disclosed herein, and alternative methods for preparing the compounds disclosed herein are deemed to be within the scope disclosed herein. For example, the synthesis of non-exemplified compounds according to the invention may be successfully performed by modifications apparent to those skilled in the art, e.g., by appropriately protecting interfering groups, by utilizing other suitable reagents known in the art other than those described, and/or by making routine modifications of reaction conditions. Alternatively, other reactions disclosed herein or known in the art will be recognized as having applicability for preparing other compounds disclosed herein.

In the examples described below, unless otherwise indicated all temperatures are set forth in degrees Celsius (° C.). Reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company, and were used without further purification unless otherwise indicated. Common solvents were purchased from commercial suppliers such as Shantou XiLong Chemical Factory, Guangdong Guanghua Reagent Chemical Factory Co. Ltd., Guangzhou Reagent Chemical Factory, Tianjin YuYu Fine Chemical Ltd., Qingdao Tenglong Reagent Chemical Ltd., and Qingdao Ocean Chemical Factory.

Column chromatography was conducted using a silica gel column. Silica gel (200-300 mesh) was purchased from Qingdao Ocean Chemical Factory. 1H NMR spectra were recorded by a Bruker Avance 400 MHz spectrometer or Bruker Avance III HD 600 spectrometer, using CDCl₃, DMSO-d₆, CD₃OD or acetone-d₆ (reported in ppm) as solvent, and using TMS (0 ppm) or chloroform (7.25 ppm) as the reference standard. When peak multiplicities are reported, the following abbreviations are used: s (singlet), d (doublet), t (triplet), m (multiplet), br (broadened), dd (doublet of doublets), dt (doublet of triplets), ddd (doublet of doublet of doublets), ddt (doublet of doublet of triplets), dddd (doublet of doublet of doublet of doublets), td (triplet of doublets), br.s (broadened singlet). Coupling constants, when given, are reported in Hertz (Hz).

Low-resolution mass spectral (MS) data were also determined on an Agilent 6320 series LC-MS spectrometer equipped with G1312A binary pumps, a G1316A TCC (Temperature Control of Column, maintained at 30° C.), a G1329A autosampler and a G1315B DAD detector were used in the analysis. An ESI source was used on the LC-MS spectrometer.

Low-resolution mass spectral (MS) data were also determined on an Agilent 6120 series LC-MS spectrometer equipped with G1311A Quaternary pump, a G1316A TCC (Temperature Control of Column, maintained at 30° C.), a G1329A autosampler and a G1315D DAD detector were used in the analysis. An ESI source was used on the LC-MS spectrometer.

Both LC-MS spectrometers were equipped with an Agilent Zorbax SB-C18, 2.1×30 mm, 5 μm column. Injection volume was decided by the sample concentration. The flow rate was 0.6 mL/min. The HPLC peaks were recorded by UV-Vis wavelength at 210 nm and 254 nm. The mobile phase was 0.1% formic acid in acetonitrile (phase A) and 0.1% formic acid in ultrapure water (phase B). The gradient condition is shown in Table 1:

TABLE 1 Gradient elution condition of low resolution mass spectrometry Time (min) A (CH₃CN, 0.1% HCOOH) B (H₂O, 0.1% HCOOH) 0-3     5-100 95-0  3-6   100  0 6-6.1 100-5 0-95 6.1-8  5 95

Purities of compounds were assessed by Agilent 1100 Series high performance liquid chromatography (HPLC) with UV detection at 210 nm and 254 nm (Zorbax SB-C18, 2.1×30 mm, 4 micorn, 10 min, 0.6 mL/min flow rate, 5 to 95% (0.1% formic acid in CH₃CN) in (0.1% formic acid in H₂O). Column was operated at 40° C.

The following abbreviations are used throughout the specification:

CDCl₃ chloroform-d DMF-d₆ N,N-dimethylformamide-d₆ DMSO-d₆ dimethyl sulfoxide-d₆ Acetone-d₆ acetone-d₆ D₂O water-d₂ EA, EtOAc ethyl acetate

DMF N,N-dimethylformamide

THF tetrahydrofuran

NMP N-methylprrolidone

MeCN, CH₃CN acetonitrile DCM, CH₂Cl₂ dichloromethane CHCl₃ chloroform CCl₄ tetrachloromethane PE petroleum ether CH₃OH, MeOH methanol g gram c concentration mol mole mmol millimole h hour, hours min minute, minutes mL milliliter v/v. v:v volume ratio DMSO dimethyl sulfoxide

NBS N-bromosuccinimide NCS N-chlorosuccinimide NIS N-iodosuccinimide EXAMPLES

The preparation methods of optically pure dihydropyrimidine compounds are disclosed in the examples of the present invention. Skilled in the art can learn from this article to properly improve the process parameters to implement the preparation method. It's to note that all the similar replacements and changes are obvious for the skilled person and within the scope of the present invention. The methods disclosed herein are described in the preferred examples. Related person can clearly realize and apply the techniques disclosed herein by making some changes, appropriate alterations or combinations to the methods without departing from spirit, principles and scope of the present disclosure.

In order to further understand the invention, it is detailed below through examples.

Example Example 1 The Preparation of (R)-ethyl 4-(2-bromo-4-fluorophenyl)-6-(morpholinomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate

Step 1) (S)-1-isopropoxy-1-oxopropan-2-yl 3-oxobutanoate

A flask was charged with (S)-isopropyl 2-hydroxypropanoate (13.2 g, 10 mmol) and 2,2,6-trimethyl-4H-1,3-dioxin-4-one (14.2 g, 10 mmol) in turn, and then equipped with distillation apparatus or water segregator. The mixture was stirred at 120° C. for 4 hours. After the reaction, the mixture was cooled and concentrated to obtain the title compound as puce liquid (15.1 g, 70%).

MS (ESI, pos.ion) m/z: 217.1 [M+H]⁺.

Step 2) (R)—(S)-1-isopropoxy-1-oxopropan-2-yl 4-(2-bromo-4-fluorophenyl)-6-methyl-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate

Method One:

To a flask were added 2-thiazolecarboxamidine hydrochloride (16.4 g, 0.1 mol), 2-bromo-4-fluorobenzaldehyde (20.3 g, 0.1 mol), (S)-1-isopropoxy-1-oxopropan-2-yl 3-oxobutanoate (21.6 g, 0.1 mol), anhydrous sodium acetate (8.2 g, 0.1 mol) and n-propanol (95 mL) in turn. The mixture was stirred at 80° C. for 16 hours. After the reaction, the mixture was cooled to 30° C., kept at 30° C. and stirred for 6 hours. The resulting mixture was filtered. The filter cake was washed with water (330 mL) and dried in vacuo at 60° C. for 8 hours to obtain the crude product. To the crude product was added n-propanol (192 g). The mixture was heated until dissolved completely, cooled to 30° C., and then kept at 30° C., stirred and crystallized for 3 hours. The resulting mixture was filtered. The filter cake was washed with n-propanol (12.8 g) and dried in vacuo at 60° C. for 8 hours to obtain the product as a yellow solid (12.2 g, 24%).

[a]_(D) ²⁵=−39.26 (c=0.2955 g/100 mL, MeOH);

MS (ESI, pos.ion) m/z: 510.0 [M+H]⁺;

¹H NMR (600 MHz, DMSO-d₆): δ 10.0 (s, 1H), 7.97 (d, 1H), 7.90 (d, 1H), 7.54 (dd, 1H), 7.37 (dd, 1H), 7.25 (td, 1H), 5.99 (s, 1H), 4.83-4.76 (m, 2H), 2.49 (s, 3H), 1.32 (d, 3H), 1.04-1.02 (m, 6H).

The compound 5 can be prepared under the reaction conditions shown in table 2 by using method one described in step 2 of Example 1.

TABLE 2 The reaction conditions

No. 1 2 3 4 5 6 7 8 (1)/(2)/(3)/(4)(mol) (the 1/1/2/1 1/1/1/1 1/1/1/1 1/1/1/1 1/1/1/1 1/1/1/1 1/1/1/1 1/1/1/1 amount of compound (1) is 16.4 g) Reaction solvent — ethanol ethanol ethanol ethanol DMF n-butanol n-propanol The mass ratio of reaction — 1 8 20 80 4.5 5 6 solvent to compound (1) Reaction temperature(° C.) 78 78 25 60 78 154 100 80 Reaction time(h) 12 12 72 24 12 1 5 12 Cooling temperature(° C.) 40 40 25 −20 −20 −10 25 40 Cooling time (h) 6 6 — 6 6 6 6 6 Recrystallization solvent ethanol ethanol ethanol ethanol ethanol n-propanol n-butanol n-propanol The mass ratio of 20 15 5 5 5 5 15 5 recrystallization solvent to compound (1) Crystallization 0 10 25 25 25 25 0 25 temperature(° C.) Crystallization time(h) 2 5 6 6 4 4 8 4 Quality; 9.95 g; 10.8 g; 12.8 g; 12.3 g; 8.9 g; 6.2 g; 9.2 g; 13.9 g; yield(%) of product 19.5 21.2 25.2 24.1 17.5 12.2 18.1 27.2 No. 9 10 11 12 13 14 15 16 (1)/(2)/(3)/(4)(mol) (the 1/1/1/1 1/1/1/1 1/1/1/1 1/1/1/1 1/1/1/1 1/1/1/1 1/1/1/1 1/1/1/1 amount of compound (1) is 16.4 g) Reaction solvent i-propanol n-propanol n-propanol ethanol ethanol t-butanol ethanol and 2-methoxy water(v/v = ethanol 50:50) The mass ratio of reaction 4.5 4.5 6 8 10 5 6 4.5 solvent to compound (1) Reaction temperature(° C.) 82 80 80 78 78 82 78 78 Reaction time(h) 12 12 12 12 12 12 12 12 Cooling temperature(° C.) 25 25 25 25 25 30 25 −10 Cooling time(h) 1 3 8 12 24 6 6 12 Recrystallization solvent i-propanol n-propanol n-propanol ethanol ethanol t-butanol ethanol i-propanol The mass ratio of 4.5 4 5 8 12 8 3.5 5 recrystallization solvent to compound (1) Crystallization 25 40 25 15 10 25 30 25 temperature(° C.) Crystallization time(h) 1 5 4 4 4 6 4 4 Quality; 9.7 g; 12.8 g; 13.9 g; 11.9 g; 10.8 g; 15.3 g; 11.4 g 10.7 g; yield(%) of product 19.1 25.1 27.3 23.3 21.2 30.0 22.4 21.0 No. 17 18 19 20 21 22 23 (1)/(2)/(3)/(4)(mol) (the 1/1/1/1 1/1/1/1 1/1/1/1 1/1/1/1 1/1/1/1 1/1/1/1 1/1/1/1 amount of compound (1) is 16.4 g) Reaction solvent 1,2-dimeth- ethyl acetone THF methanol 2-methoxy ethyl oxyethane acetate ethyl ether acetate The mass ratio of reaction 4.5 3 3 3 4 5 3 solvent to compound (1) Reaction temperature(° C.) 78 77 56 65 64 78 77 Reaction time(h) 12 12 12 12 12 6 12 Cooling temperature(° C.) −10 −10 −10 −10 10 −10 −10 Cooling time(h) 12 12 12 12 6 12 12 Recrystallization solvent n-propanol i-propanol i-propanol i-propanol n-propanol n-propanol ethyl acetate The mass ratio of 5 6 5 5 5 5 2 recrystallization solvent to compound (1) Crystallization 25 25 25 25 25 25 −10 temperature(° C.) Crystallization time(h) 4 4 4 4 4 6 8 Quality; 6.8 g; 8.6 g; 4.4 g; 3.4 g; 9.0 g; 5.1 g; 5.7 g; yield(%) of product 13.3 16.9 8.7 6.6 17.7 10.0 11.1

Method Two:

To a flask were added 2-thiazolecarboxamidine hydrochloride (16.4 g, 0.1 mol), 2-bromo-4-fluorobenzaldehyde (20.3 g, 0.1 mol), (S)-1-isopropoxy-1-oxopropan-2-yl 3-oxobutanoate (21.6 g, 0.1 mol), anhydrous sodium acetate (8.2 g, 0.1 mol) and ethanol (95 mL) in turn. The mixture was stirred at 80° C. for 16 hours. After the reaction, the mixture was cooled to 30° C., kept at 30° C. and stirred for 6 hours. The resulting mixture was filtered. The filter cake was washed with ethanol (124 mL) followed by water (330 mL), and then dried in vacuo at 60° C. for 8 hours to obtain the product as a yellow solid (15 g, 29%).

[a]_(D) ²⁵=−39.26 (c=0.2955 g/100 mL, MeOH);

MS (ESI, pos.ion) m/z: 510.0 [M+H]⁺;

¹H NMR (600 MHz, DMSO-d₆): δ 10.0 (s, 1H), 7.97 (d, 1H), 7.90 (d, 1H), 7.54 (dd, 1H), 7.37 (dd, 1H), 7.25 (td, 1H), 5.99 (s, 1H), 4.83-4.76 (m, 2H), 2.49 (s, 3H), 1.32 (d, 3H), 1.04-1.02 (m, 6H).

The compound 5 can be prepared under the reaction conditions shown in table 3 by using method two described in step 2 of Example 1

TABLE 3 The reaction conditions

No. 1 2 3 4 5 6 7 8 (1)/(2)/(3)/(4)(mol) (the 1/1/2/1 1/1/1/1 1/1/1/1 1/1/1/1 1/1/1/1 1/1/1/1 1/1/1/1 1/1/1/1 amount of compound (1) is 16.4 g) Reaction solvent — ethanol ethanol ethanol ethanol DMF n-butanol n-propanol The mass ratio of reaction — 1 8 20 80 4.5 5 6 solvent to compound (1) Reaction temperature(° C.) 78 78 30 60 78 154 100 80 Reaction time(h) 12 12 72 24 12 1 5 12 Cooling temperature(° C.) 40 40 30 −20 −20 −10 25 40 Cooling time(h) 6 6 — 6 6 6 6 6 Washing solvent ethanol ethanol ethanol ethanol — DMF n-butanol n-propanol The mass ratio of washing 16 10 5 2 — 1 12 5 solvent to compound (1) Washing temperature 25 25 25 25 — 25 25 25 Quality; 10.4 g; 12.0 g; 13.5 g; 12.9 g; 9.7 g; 6.7 g; 9.6 g; 15.3 g; yield(%) of product 20.3 23.6 26.5 25.3 19.1 13.1 18.9 30.0 No. 9 10 11 12 13 14 15 16 (1)/(2)/(3)/(4)(mol) (the 1/1/1/1 1/1/1/1 1/1/1/1 1/1/1/1 1/1/1/1 1/1/1/1 1/1/1/1 1/1/1/1 amount of compound (1) is 16.4 g) Reaction solvent i-propanol n-propanol n-propanol ethanol ethanol t-butanol ethanol and 2-methoxy water(v/v = ethanol 50:50) The mass ratio of reaction 4.5 6 6 8 10 5 6 4.5 solvent to compound (1) Reaction temperature(° C.) 82 80 80 78 78 82 78 78 Reaction time(h) 12 12 12 12 12 12 12 12 Cooling temperature(° C.) 25 25 25 25 25 30 25 −10 Cooling time(h) 1 3 8 12 24 6 6 12 Washing solvent i-propanol n-propanol n-propanol ethanol ethanol t-butanol ethanol and 2-methoxy water(v/v = ethanol 50:50) The mass ratio of 6 6 5 8 10 8 8 1 washing solvent to compound (1) Washing temperature 25 25 25 25 25 30 25 0 Quality; 10.1 g; 14.9 g; 15.4 g; 12.9 g; 11.8 g; 15.9 g; 12.4 g; 11.7 g; yield(%) of product 19.8 29.2 30.2 25.3 23.2 31.1 24.3 23.0 No. 17 18 19 20 21 22 (1)/(2)/(3)/(4)(mol) (the 1/1/1/1 1/1/1/1 1/1/1/1 1/1/1/1 1/1/1/1 1/1/1/1 amount of compound (1) is 16.4 g) Reaction solvent 1,2-dimeth- ethyl acetone THF methanol 2-methoxy oxyethane acetate ethyl ether The mass ratio of reaction 4.5 3 3 3 4 5 solvent to compound (1) Reaction temperature(° C.) 78 77 56 65 64 78 Reaction time(h) 12 12 12 12 12 6 Cooling temperature(° C.) −10 −10 −10 −10 25 −10 Cooling time(h) 12 12 12 12 6 12 Washing solvent 2-methoxy ethyl acetone THF methanol n-propanol ethyl ether acetate The mass ratio of 1 1 1 1 3 4 washing solvent to compound (1) Washing temperature 0 0 0 0 25 20 Quality; 7.6 g; 9.2 g; 5.1 g; 3.6 g; 9.95 g; 5.5 g; yield(%) of product 15.0 18.0 10.0 7.0 19.5 10.8

Method Three:

To a flask were added 2-thiazolecarboxamidine hydrochloride (16.4 g, 0.1 mol), 2-bromo-4-fluorobenzaldehyde (20.3 g, 0.1 mol), (S)-1-isopropoxy-1-oxopropan-2-yl 3-oxobutanoate (21.6 g, 0.1 mol), anhydrous sodium acetate (8.2 g, 0.1 mol) and ethanol (95 mL) in turn. The mixture was stirred at 80° C. for 16 hours. After the reaction, the mixture was cooled to 30° C., kept at 30° C. and stirred for 6 hours. The resulting mixture was filtered. The filter cake was washed with water (330 mL), and then dried in vacuo at 60° C. for 8 hours to obtain the crude product. The crude product was triturated with ethanol (100 g) at 30° C. for 3 hours and filtered. The filter cake was dried in vacuo at 60° C. for 8 hours to obtain the product as a yellow solid (15.3 g, 30%).

[a]_(D) ²⁵=−39.26 (c=0.2955 g/100 mL, MeOH);

MS (ESI, pos.ion) m/z: 510.0 [M+H]⁺;

¹H NMR (600 MHz, DMSO-d₆): δ 10.0 (s, 1H), 7.97 (d, 1H), 7.90 (d, 1H), 7.54 (dd, 1H), 7.37 (dd, 1H), 7.25 (td, 1H), 5.99 (s, 1H), 4.83-4.76 (m, 2H), 2.49 (s, 3H), 1.32 (d, 3H), 1.04-1.02 (m, 6H).

The compound 5 can be prepared under the reaction conditions shown in table 4 by using method three described in step 2 of Example 1

TABLE 4 The reaction conditions

No. 1 2 3 4 5 6 7 8 (1)/(2)/(3)/(4)(mol) (the 1/1/2/1 1/1/1/1 1/1/1/1 1/1/1/1 1/1/1/1 1/1/1/1 1/1/1/1 1/1/1/1 amount of compound (1) is 16.4 g) Reaction solvent — ethanol ethanol ethanol ethanol DMF n-butanol n-propanol The mass ratio of reaction — 1 8 20 80 4.5 5 6 solvent to compound (1) Reaction temperature(° C.) 78 78 30 60 78 154 100 80 Reaction time(h) 12 12 72 24 12 1 5 12 Cooling temperature(° C.) 40 40 30 −20 −20 −10 25 40 Cooling time(h) 6 6 — 6 6 6 6 6 Trituration solvent ethanol ethanol ethanol ethanol ethanol n-propanol n-butanol n-propanol The mass ratio of 18 15 4 5 2 5 20 5 trituration solvent to compound (1) Trituration temperature 25 25 40 25 25 25 25 25 (° C.) Trituration time(h) 3 4 4 5 6 7 6 12 Quality; 10.2 g; 11.3 g; 13.1 g; 12.6 g; 9.3 g; 6.4 g; 9.4 g; 14.2 g; yield(%) of product 19.9 22.1 25.7 24.6 18.2 12.6 18.4 27.9 No. 9 10 11 12 13 14 15 16 (1)/(2)/(3)/(4)(mol) (the 1/1/1/1 1/1/1/1 1/1/1/1 1/1/1/1 1/1/1/1 1/1/1/1 1/1/1/1 1/1/1/1 amount of compound (1) is 16.4 g) Reaction solvent i-propanol n-propanol n-propanol ethanol ethanol t-butanol ethanol and 2-methoxy water(v/v = ethanol 50:50) The mass ratio of reaction 4.5 4.5 6 8 10 5 6 4.5 solvent to compound (1) Reaction temperature(° C.) 82 80 80 78 78 82 78 78 Reaction time(h) 12 12 12 12 12 12 12 12 Cooling temperature(° C.) 25 25 25 25 25 30 25 −10 Cooling time(h) 1 3 8 12 24 6 6 12 Trituration solvent i-propanol ethanol n-propanol ethanol ethanol t-butanol ethanol i-propanol The mass ratio of 6 15 7 8 10 8 8 6 trituration solvent to compound (1) Trituration temperature(° C.) 25 5 25 25 25 25 25 25 Trituration time(h) 8 1 7 12 10 8 6 6 Quality; 9.9 g; 12.0 g; 14.4 g; 12.7 g; 11.5 g; 15.2 g; 11.6 g; 11.3 g; yield(%) of product 19.4 23.5 28.3 24.8 22.6 29.9 22.7 22.1 No. 17 18 19 20 21 22 23 (1)/(2)/(3)/(4)(mol) (the 1/1/1/1 1/1/1/1 1/1/1/1 1/1/1/1 1/1/1/1 1/1/1/1 1/1/1/1 amount of compound (1) is 16.4 g) Reaction solvent 1,2-dimeth- ethyl acetone THF methanol 2-methoxy n-propanol oxyethane acetate ethyl ether The mass ratio of reaction 4.5 3 3 3 4 5 4.5 solvent to compound (1) Reaction temperature(° C.) 78 77 56 65 64 78 80 reaction time(h) 12 12 12 12 12 6 12 cooling temperature(° C.) −10 −10 −10 −10 25 −10 25 Cooling time(h) 12 12 12 12 6 12 3 Trituration solvent n-propanol i-propanol ethanol i-propanol n-propanol n-propanol ethanol The mass ratio of 5 6 3 3 5 4 15 trituration solvent to compound (1) Trituration temperature(° C.) 25 25 25 25 25 25 10 Trituration time(h) 5 5 2 4 5 4 1 Quality; 7.3 g; 8.8 g; 4.7 g; 3.5 g; 9.4 g; 5.3 g; 11.2 g; yield(%) of product 14.3 17.3 9.3 6.9 18.4 10.3 22

Step 3) (R)—(S)-1-isopropoxy-1-oxopropan-2-yl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate

To a flask were added (R)—(S)-1-isopropoxy-1-oxopropan-2-yl 4-(2-bromo-4-fluorophenyl)-6-methyl-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (51 g, 0.1 mol) and dichloromethane (1360 g). The mixture was heated at 35±5° C. under nitrogen atmosphere until dissolved completely, and then to the mixture was added NBS (19.6 g, 0.11 mol) The mixture was kept at this temperature and stirred for 30 min. After the reaction, the reaction mixture was concentrated. To the residue was added ethanol (255 g). The resulting mixture was cooled to 0° C., kept at this temperature and stirred. After solid precipitated out completely, the mixture was filtered. The filter cake was washed with ethanol (40 g) and dried in vacuo at 60° C. for 6 hours to obtain the product as a yellow solid (38.9 g, 66%).

MS (ESI, pos.ion) m/z: 588.0 [M+H]⁺;

¹H NMR (600 MHz, DMSO-d₆): δ 10.40 (s, 1H), 8.02 (d, 1H), 7.94 (d, 1H), 7.58 (dd, 1H), 7.42 (dd, 1H), 7.28 (td, 1H), 6.08 (s, 1H), 4.92-4.57 (m, 4H), 1.38 (d, 3H), 1.02 (d, 6H).

The compound A1 can be prepared under the reaction conditions shown in table 5 according to the procedure described in step 3 of Example 1

TABLE 5 The reaction conditions

No. 1 2 3 4 Compound (5)/NBS(mol) the 1/1.1 1/1.05 1/1.15 1/1.1 amount of compound (5) is 51 g Reaction solvent DCM DCM CHCl₃ CCl₄ The mass ratio of reaction 30 15 20 20 solvent to compound (5) Reaction temperature(° C.) 39 39 61 76 The solvent added to the residue i-propanol ethanol n-propanol ethanol The mass ratio of the additional 7 5 6 5 solvent to compound (5) Quality; 40.6 g; 38.3 g; 37.7 g; 44.7 g; yield(%) of product 69 65 64 76

Step 4) (R)—(S)-1-isopropoxy-1-oxopropan-2-yl 4-(2-bromo-4-fluorophenyl)-6-(morpholinomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate

To a flask were added (R)—(S)-1-isopropoxy-1-oxopropan-2-yl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (58.9 g, 0.1 mol), i-propanol (353 g) and morpholine (34.8 g, 0.4 mol). The mixture was stirred at 55° C. for 4 hours. After the reaction, the mixture was cooled to 0° C., kept at this temperature and stirred. After the solid precipitated out completely, the mixture was filtered. The filter cake was washed with i-propanol (58.9 g) followed by water (590 g), and then dried in vacuo at 60° C. for 8 hours to obtain the product as a yellowish solid (41.7 g, 70%).

MS (ESI, pos.ion) m/z: 595.1 [M+H]⁺;

¹H NMR (600 MHz, DMSO-d₆): δ 9.77 (s, 1H), 8.04 (d, 1H), 7.96 (d, 1H), 7.56 (dd, 1H), 7.41 (dd, 1H), 7.23 (td, 1H), 6.06 (s, 1H), 4.86 (q, 1H), 4.82-4.76 (m, 1H), 3.98 (dd, 2H), 3.68 (brs, 4H), 2.57-2.52 (m, 4H), 1.34 (d, 3H), 1.04 (d, 6H).

Step 5) (R)-ethyl 4-(2-bromo-4-fluorophenyl)-6-(morpholinomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate

To a flask were added anhydrous ethanol (446 g) and lithium (1.74 g, 0.25 mol) in turn. The mixture was stirred at 43° C. until the lithium was consumed entirely, and then a solution of (R)—(S)-1-isopropoxy-1-oxopropan-2-yl 4-(2-bromo-4-fluorophenyl)-6-(morpholinomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (59.5 g, 0.1 mol) in ethanol (446 g) was added. The reaction mixture was allowed to warm up to 78° C. and stirred for 1.5 hours. After the reaction, the reaction mixture was cooled and concentrated. To the residue was added ethyl acetate (595 g). The mixture was washed with water (200 g×2). The combined organic layers were concentrated to obtain the product as a yellow solid (38.2 g, 75%).

MS (ESI, pos.ion) m/z: 509.1 [M+H]⁺;

¹H NMR (600 MHz, DMSO-d₆): δ 9.69 (s, 1H), 8.02 (d, 1H), 7.93 (d, 1H), 7.57 (dd, 1H), 7.40 (dd, 1H), 7.22 (td, 1H), 6.05 (s, 1H), 3.96 (q, 2H), 3.93 (dd, 2H), 3.68 (br, 4H), 2.56 (br, 4H), 1.05 (t, 3H).

Example 2 The Preparation of (R)-methyl 4-(2-bromo-4-fluorophenyl)-6-(morpholinomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate

To a flask were added anhydrous methanol (892 g) and lithium (1.74 g, 0.25 mol) in turn. The mixture was stirred at 43° C. until the lithium was consumed entirely, and then (R)—(S)-1-isopropoxy-1-oxopropan-2-yl 4-(2-bromo-4-fluorophenyl)-6-(morpholinomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (59.5 g, 0.1 mol) was added. The reaction mixture was allowed to warm up to 60° C. and stirred for 1.5 hours. After the reaction, the reaction mixture was cooled and concentrated. To the residue was added ethyl acetate (595 g). The mixture was washed with water (200 mL×2). The combined organic layers were concentrated to obtain the product as yellow thick oil (34.7 g, 70%).

MS (ESI, pos.ion) m/z: 494.7 [M+H]⁺;

¹H NMR (600 MHz, DMSO-d₆): δ 9.71 (s, 1H), 8.02 (d, 1H), 7.94 (d, 1H), 7.55 (dd, 1H), 7.37 (dd, 1H), 7.20 (td, 1H), 6.02 (s, 1H), 3.91 (dd, 2H), 3.67 (br, 4H), 3.52 (s, 3H), 2.55 (br, 4H).

Example 3 The Preparation of (R)-3-(morpholin-3-yl)propanoic acid hydrochloride

Step 1) (S)-tert-butyl 3-formylmorpholine-4-carboxylate

To a flask were added (R)-tert-butyl 3-(hydroxymethyl)morpholine-4-carboxylate (1.47 g, 6.77 mmol) and DCM (30 mL) in turn, and then Dess-Martin periodinane (3.44 g, 8.12 mmol) was added at 0° C. The mixture was stirred at 0° C. for 1 hour. After the reaction, the mixture was quenched with saturated aqueous sodium bicarbonate (30 mL) and separated. The organic layer was washed with saturated aqueous sodium bicarbonate (30 mL×3) and saturated aqueous sodium chloride (30 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was used directly at next operation.

Step 2) (R)-tert-butyl 3-(3-ethoxy-3-oxoprop-1-en-1-yl)morpholine-4-carboxylate

To a flask were added (S)-tert-butyl 3-formylmorpholine-4-carboxylate (1.46 g, 6.77 mmol), DCM (40 mL) and ethyl (triphenylphosphoranylidene)acetate (2.36 g, 6.77 mmol) in turn. The mixture was stirred at 25° C. for 12 hours. After the reaction, the mixture was filtered. The filtrate was concentrated. The residue was purified by silica gel chromatography eluted with PE/EtOAc (V/V)=10/1 to give the product as a colorless oil (1.05 g, 54%).

MS (ESI, pos.ion) m/z: 186.1 [M+H−100]⁺;

¹H NMR (400 MHz, CDCl₃): δ 6.69 (dd, 1H), 5.89 (dd, 1H), 4.56 (s, 1H), 4.20-4.12 (m, 2H), 3.94-3.82 (m, 2H), 3.77-3.65 (m, 2H), 353-3.43 (m, 1H), 3.27-3.10 (m, 1H), 1.41 (s, 9H), 1.29-1.23 (m, 3H).

Step 3) (R)-tert-butyl 3-(3-ethoxy-3-oxopropyl)morpholine-4-carboxylate

To a flask were added (R)-tert-butyl 3-(3-ethoxy-3-oxoprop-1-en-1-yl)morpholine-4-carboxylate (1.05 g, 3.68 mmol), anhydrous ethanol (20 mL) and Pd—C (10%, 0.2 g) in turn. The mixture was stirred at 30° C. under hydrogen atmosphere overnight and filtered. The filtrate was concentrated to give the product as colorless oil (0.96 g, 91%).

MS (ESI, pos.ion) m/z: 188.1[M+H−100]⁺;

¹H NMR (400 MHz, CDCl₃): δ 4.12 (q, 2H), 3.98 (s, 1H), 3.84-3.69 (m, 3H), 3.56 (dd, 1H), 3.42 (td, 1H), 3.12 (t, 1H), 2.37-2.27 (m, 2H), 2.25-2.15 (m, 1H), 1.92-1.83 (m, 1H), 1.45 (s, 9H), 1.25 (t, 3H).

Step 4) (R)-3-(4-(tert-butoxycarbonyl)morpholin-3-yl)propanoic acid

To a flask were added (R)-tert-butyl 3-(3-ethoxy-3-oxopropyl)morpholine-4-carboxylate (0.96 g, 3.34 mmol), anhydrous ethanol (10 mL) and a solution of lithium hydroxide hydrate (1.4 g, 33.4 mmol) in water (10 mL) in turn. The mixture was stirred at 25° C. for 30 min. After the reaction, to the reaction mixture was added ethyl acetate (150 mL) and water (50 mL). The resulting mixture was adjusted to pH 5-6 with concentrated hydrochloric acid at 0° C. After the mixture was partitioned. The organic layer was washed with saturated aqueous sodium chloride (100 mL), dried over anhydrous sodium sulfate and concentrated to give the product as colorless oil (0.85 g, 98%).

MS (ESI, pos.ion) m/z: 160.1[M+H−100]⁺;

¹H NMR (400 MHz, CDCl₃): δ 8.08 (br, 1H), 4.03 (brs, 1H), 3.88-3.72 (m, 3H), 3.58 (dd, 1H), 3.44 (td, 1H), 3.13 (t, 1H), 2.43-2.29 (m, 2H), 2.27-2.20 (m, 1H), 1.94-1.83 (m, 1H), 1.46 (s, 9H).

Step 5) (R)-3-(morpholin-3-yl)propanoic acid hydrochloride

To a flask were added (R)-3-(4-(tert-butoxycarbonyl)morpholin-3-yl)propanoic acid (0.9 g, 3.47 mmol) and a solution of hydrogen chloride in ethyl acetate (4 mol/L, 15 mL) in turn. The mixture was stirred at 25° C. for 4 hours. After the reaction, the mixture was filtered to give the product as a white solid (0.53 g, 78%).

MS (ESI, pos.ion) m/z: 160.1[M+H]⁺;

¹H NMR (400 MHz, D₂O): δ 4.04-3.96 (m, 2H), 3.75-3.68 (m, 1H), 3.52 (dd, 1H), 3.40-3.35 (m, 1H), 3.34-3.29 (m, 1H), 3.22-3.15 (m, 1H), 2.47 (t, 2H), 1.83 (ddd, 2H).

The compound VI hydrochloride can be prepared under the reaction conditions shown in table 6 according to the procedure described in Example 3.

TABLE 6 The reaction conditions for preparation of the compound (VI) hydrochloride Raw material The amount of raw material

  hydrochloride Product character Quality; yield(%) of product

50 g

white solid 23 g; 51

50 g

white solid 21.2 g; 47

50 g

white solid 18.5 g; 41

50 g

white solid 17.8 g; 39

50 g

gray solid 16.4 g; 36

50 g

gray solid 17.3 g; 38

TABLE 6-1 The NMR and MS datum of the compound (VI) hydrochloride

            NMR             MS

¹H NMR (400 MHz, D₂O): δ 4.03 (dd, 1H), 3.78-3.67 (m, 2H), 3.25 (t, 2H), 3.08 (td, 1H), 2.85 (dd, 1H), 2.27-2.23 (m, 2H), 1.73-1.67 (m, 2H). MS (ESI, neg.ion) m/z: 158.2[M − H]⁻

¹H NMR (400 MHz, D₂O): δ 4.10-4.02 (m, 1H), 3.80-3.74 (m, 2H), 3.32-3.25 (m, 2H), 3.10 (td, 1H), 2.89 (t, 1H), 2.47-2.43 (m, 2H), 1.88-1.70 (m, 2H). MS (ESI, pos.ion) m/z: 160.1 [M + H]⁺

¹H NMR (400 MHz, D₂O): δ 4.07-3.98 (m, 2H), 3.78-3.71 (m, 1H), 3.55 (dd, 1H), 3.43-3.38 (m, 1H), 3.35 (dt, 1H), 3.24-3.17 (m, 1H), 2.50 (t, 2H), 1.89-1.83 (m, 2H). MS (ESI, pos.ion) m/z: 160.3 [M + H]⁺

¹H NMR (600 MHz, D₂O): δ 4.05 (dd, 1H), 3.84-3.79 (m, 1H), 3.74-3.70 (m, 1H), 3.34 (d, 1H), 3.21 (td, 1H), 3.10 (td, 1H), 2.55 (t, 2H), 2.06-2.03 (m, 1H), 1.82-1.76 (m, 1H), 1.26 (d, 3H). MS (ESI, pos.ion) m/z: 174.3 [M + H]⁺

¹H NMR (600 MHz, DMSO-d₆): δ 10.21 (br, 1H), 3.80-3.73 (m, 2H), 3.66-3.59 (m, 1H), 2.74-2.67 (m, 1H), 2.43-2.40 (m, 2H), 2.33-2.23 (m, 1H), 2.05-1.95 (m, 2H). MS (ESI, pos.ion) m/z: 180.2 [M + H]⁺

¹H NMR (600 MHz, D₂O): δ 4.00-3.94 (m, 1H), 3.82 (dd, 1H), 3.72 (dd, 1H), 2.83-2.76 (m, 1H), 2.57-2.47 (m, 2H), 2.39-2.32 (m, 1H), 2.16-2.03 (m, 2H). MS (ESI, pos.ion) m/z: 180.2 [M + H]⁺

Example 4 The Preparation of (2R,3S)-2-methylmorpholine-3-carboxylic acid

The title compound ((2R,3S)-2-methylmorpholine-3-carboxylic acid) was prepared according to the procedure described in example 34 of patent WO2014029193.

MS (ESI, pos.ion) m/z: 146.2[M+H]⁺;

¹H NMR (600 MHz, D₂O): δ 4.01-3.98 (m, 1H), 3.82-3.77 (m, 1H), 3.76-3.72 (m, 1H), 3.37 (d, 1H), 3.27-3.24 (m, 1H), 3.19-3.14 (m, 1H), 1.26 (d, 3H).

Example 5 The Preparation of (S)-4-(((R)-6-(2-bromo-4-fluorophenyl)-5-(ethoxycarbonyl)-2-(thiazol-2-yl)-3,6-dihydropyrimidin-4-yl)methyl)morpholine-3-carboxylic acid

Step 1) (S)-4-(((R)-6-(2-bromo-4-fluorophenyl)-5-((((S)-1-isopropoxy-1-oxopropan-2-yl)oxy)carbonyl)-2-(thiazol-2-yl)-3,6-dihydropyrimidin-4-yl)methyl)morpholine-3-carboxylic acid

To a flask were added (R)—(S)-1-isopropoxy-1-oxopropan-2-yl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (58.9 g, 0.1 mol), ethanol (589 g), (S)-morpholine-3-carboxylic acid (13.1 g, 0.1 mol) and potassium carbonate (27.6 g, 0.2 mol) in turn. The mixture was stirred at 30° C. under nitrogen atmosphere for 12 hours. After the reaction, the mixture was filtered. The filtrate was concentrated. To the residue was added water (900 g), the resulting mixture was extracted with ethyl acetate (450 mL×3), the organic layers were abandoned. To the aqueous layer was added ethyl acetate (900 mL), the mixture was adjusted to pH 3-6 with concentrated hydrochloric acid. The organic layer was dried over anhydrous sodium sulfate and concentrated to give the product as a yellow solid (46 g, 72%).

MS (ESI, pos.ion) m/z: 638.5 [M+H]⁺;

¹H NMR (400 MHz, DMSO-d₆): δ 12.79 (br, 1H), 9.92 (s, 1H), 8.04 (d, 1H), 7.95 (d, 1H), 7.55 (dd, 1H), 7.43 (dd, 1H), 7.21 (td, 1H), 6.05 (s, 1H), 4.86 (q, 1H), 4.82-4.76 (m, 1H), 4.31 (d, 1H), 4.05-4.01 (m, 2H), 3.83 (dd, 1H), 3.75-3.72 (m, 1H), 3.68-3.64 (m, 2H), 3.13-3.05 (m, 1H), 2.43-2.37 (m, 1H), 1.34 (d, 3H), 1.03 (t, 6H).

The compound E can be prepared under the reaction conditions shown in table 7 according to the procedure described in step 1 of Example 5.

TABLE 7 The reaction conditions for preparation of compound E

                No.

  or a hydrochloride thereof         CompoundA1/ compound(VI)(mol) the amount of compound A1 is 11.8 g               Reaction solvent             Reaction temperature (° C.)               Reaction time(h)               Product character             Quality; yield(%) of product E1

1/1 ethanol 30 12 yellow solid 9.34 g; 70 E2

1/1 ethanol 30 12 yellow solid 9.75 g; 73 E3

1/1 ethanol 30 12 yellow solid 8.68 g; 65 E4

1/1 ethanol 30 12 yellow solid 7.34 g; 55 E5

1/1 ethanol 30 12 yellow solid 9.8 g; 75 E6

1/1 ethanol 30 12 yellow solid 6.81 g; 50 E7

1/1 ethanol 30 12 yellow solid 9.89 g; 75 E8

1/1 ethanol 30 12 yellow solid 7.43 g; 54 E9

1/1 ethanol 30 12 yellow solid 6.74 g; 49

TABLE 7-1 The NMR and MS datum of compound E No. ¹H NMR MS E1 ¹H NMR (400 MHz, DMSO-d₆): δ 12.03 (s, 1H), 9.74 (s, 1H), 8.02 (d, 1H), MS (ESI, pos. ion) 7.95 (d, 1H), 7.55 (dd, 1H), 7.41 (dd, 1H), 7.23 (td, 1H), 6.05 (s, 1H), m/z: 667.2 [M + H]⁺ 4.89-4.75 (m, 2H), 3.99-3.87 (m, 3H), 3.61-3.56 (m, 1H), 3.53-3.47 (m, 1H), 2.78 (dd, 2H), 2.38-2.25 (m, 3H), 2.02 (t, 1H), 1.65-1.60 (m, 2H), 1.34 (d, 3H), 1.03 (dd, 6H). E2 ¹H NMR (400 MHz, DMSO-d₆): δ 12.07 (s, 1H), 9.76 (s, 1H), 8.01 (d, 1H), MS (ESI, pos. ion) 7.96 (d, 1H), 7.56 (dd, 1H), 7.42 (dd, 1H), 7.27 (td, 1H), 6.05 (s, 1H), m/z: 666.5 [M + H]⁺ 4.92-4.85 (m, 1H), 4.81-4.75 (m, 1H), 3.97-3.86 (m, 3H), 3.62-3.57 (m, 1H), 3.54-3.48 (m, 1H), 2.77 (dd, 2H), 2.39-2.25 (m, 3H), 2.03 (t, 1H), 1.66-1.61 (m, 2H), 1.35 (d, 3H), 1.04 (dd, 6H). E3 ¹H NMR (400 MHz, DMSO-d₆): δ 12.07 (s, 1H), 9.90 (s, 1H), 8.04 (d, 1H), MS (ESI, pos. ion) 7.96 (d, 1H), 7.55 (dd, 1H), 7.42 (dd, 1H), 7.22 (td, 1H), 6.05 (s, 1H), m/z: 667.2 [M + H]⁺ 4.89-4.76 (m, 2H), 4.24 (d, 1H), 3.92-3.85 (m, 1H), 3.82-3.69 (m, 2H), 3.67-3.58 (m, 1H), 3.45-3.40 (m, 1H), 2.89-2.75 (m, 2H), 2.61-2.56 (m, 1H), 2.33-2.21 (m, 2H), 1.78-1.72 (m, 1H), 1.65-1.57 (m, 1H), 1.35 (d, 3H), 1.03 (dd, 6H). E4 ¹H NMR (400 MHz, DMSO-d₆): δ 12.12 (s, 1H), 9.90 (s, 1H), 8.04 (d, 1H), MS (ESI, pos. ion) 7.96 (d, 1H), 7.55 (dd, 1H), 7.43 (dd, 1H), 7.22 (td, 1H), 6.05 (s, 1H), m/z: 667.2 [M + H]⁺ 4.89-4.75 (m, 2H), 4.17 (d, 1H), 3.93-3.73 (m, 3H), 3.65-3.55 (m, 1H), 3.40-3.36 (m, 1H), 2.85-2.75 (m, 1H), 2.58-2.55 (m, 2H), 2.38-2.25 (m, 2H), 1.85-1.80 (m, 1H), 1.68-1.58 (m, 1H), 1.35 (d, 3H), 1.03 (dd, 6H). E5 ¹H NMR (400 MHz, DMSO-d₆): δ 13.00 (s, 1H), 9.89 (s, 1H), 8.03 (d, 1H), MS (ESI, pos. ion) 7.94 (d, 1H), 7.55 (dd, 1H), 7.41 (dd, 1H), 7.23 (td, 1H), 6.03 (s, 1H), m/z: 653.2 [M + H]⁺ 4.87-4.75 (m, 2H), 4.05 (d, 1H), 3.93-3.87 (m, 1H), 3.78-3.61 (m, 3H), 3.41-3.38 (m, 1H), 3.01 (d, 1H), 2.93 (d, 1H), 1.33 (d, 3H), 1.22 (d, 3H), 1.03 (dd, 6H). E6 ¹H NMR (400 MHz, DMSO-d₆): δ 12.08 (s, 1H), 9.89 (s, 1H), 8.04 (d, 1H), MS (ESI, pos. ion) 7.94 (d, 1H), 7.56 (dd, 1H), 7.42 (dd, 1H), 7.21 (td, 1H), 6.04 (s, 1H), m/z: 682.1 [M + H]⁺ 4.88-4.78 (m, 2H), 4.18 (d, 1H), 3.84 (d, 1H), 3.76-3.74 (m, 1H), 3.58-3.55 (m, 1H), 3.51-3.46 (m, 1H), 2.68 (d, 1H), 2.45-2.40 (m, 1H), 2.38-2.31 (m, 3H), 2.06-1.88 (m, 1H), 1.79-1.71 (m, 1H), 1.31 (d, 3H), 1.21 (d, 3H), 1.06 (dd, 6H). E7 ¹H NMR (400 MHz, DMSO-d₆): δ 10.16 (s, 1H), 7.97 (d, 1H), 7.91 (d, 1H), MS (ESI, pos. ion) 7.55 (dd, 1H), 7.44 (dd, 1H), 7.23 (td, 1H), 6.02 (s, 1H), 4.87-4.76 (m, 2H), m/z: 658.5 [M + H]⁺ 4.33 (d, 1H), 4.11 (d, 1H), 3.83-3.75 (m, 1H), 3.55-3.47 (m, 2H), 3.12-3.06 (m, 1H), 2.75-2.65 (m, 1H), 1.34 (d, 3H), 1.03 (d, 6H). E8 ¹H NMR (400 MHz, DMSO-d₆): δ 12.05 (s, 1H), 9.58 (s, 1H), 8.00 (d, 1H), MS (ESI, pos. ion) 7.94 (d, 1H), 7.55 (dd, 1H), 7.44 (dd, 1H), 7.24 (td, 1H), 6.04 (s, 1H), m/z: 689.1 [M + H]⁺ 4.85 (q, 1H), 4.82-4.76 (m, 1H), 4.13 (dd, 2H), 3.67-3.58 (m, 1H), 3.05-2.84 (m, 2H), 2.63-2.56 (m, 1H), 2.33-2.18 (m, 2H), 2.15-1.99 (m, 1H), 1.95-1.85 (m, 1H), 1.58-1.48 (m, 1H), 1.34 (d, 3H), 1.03 (d, 6H). E9 ¹H NMR (400 MHz, DMSO-d₆): δ 9.52 (s, 1H), 8.00 (d, 1H), 7.93 (d, 1H), MS (ESI, pos. ion) 7.55 (dd, 1H), 7.45 (dd, 1H), 7.23 (td, 1H), 6.05 (s, 1H), 4.84 (q, 1H), m/z: 687.2 [M + H]⁺ 4.81-4.75 (m, 1H), 4.12 (dd, 2H), 3.66-3.57 (m, 1H), 3.03-2.95 (m, 1H), 2.92-2.84 (m, 1H), 2.63-2.57 (m, 1H), 2.39-2.24 (m, 2H), 2.15-1.98 (m, 2H), 1.66-1.57 (m, 1H), 1.34 (d, 3H), 1.02 (d, 6H).

Step 2) (S)-4-(((R)-6-(2-bromo-4-fluorophenyl)-5-(ethoxycarbonyl)-2-(thiazol-2-yl)-3,6-dihydropyrimidin-4-yl)methyl)morpholine-3-carboxylic acid

To a flask were added anhydrous ethanol (650 g) and lithium (1.74 g, 0.25 mol) in turn. The mixture was stirred at 43° C. until the lithium was consumed entirely, and then (S)-4-(((R)-6-(2-bromo-4-fluorophenyl)-5-((((S)-1-isopropoxy-1-oxopropan-2-yl)oxy)carbonyl)-2-(thiazol-2-yl)-3,6-dihydropyrimidin-4-yl)methyl)morpholine-3-carboxylic acid (63.9 g, 0.1 mol) was added. The reaction mixture was allowed to warm up to 78° C. and stirred for 12 hours. After the reaction, the reaction mixture was cooled and concentrated. To the residue was added water (1280 g), the mixture was extracted with ethyl acetate (1000 mL×1). The mixture was partitioned. The organic layer was abandoned. To the aqueous layer was added ethyl acetate (1280 mL), the mixture was adjusted to pH 3-6 with concentrated hydrochloric acid. The organic layer was dried over anhydrous sodium sulfate and concentrated to give the product as a yellow solid (38.2 g, 69%).

MS (ESI, pos.ion) m/z: 553.2[M+H];

¹H NMR (400 MHz, DMSO-d₆): δ 12.85 (br, 1H), 9.80 (s, 1H), 8.00 (d, 1H), 7.91 (d, 1H), 7.54 (dd, 1H), 7.39 (dd, 1H), 7.19 (td, 1H), 6.01 (s, 1H), 4.25 (d, 1H), 4.02 (d, 1H), 3.97-3.91 (m, 3H), 3.81 (dd, 1H), 3.72-3.69 (m, 1H), 3.66-3.63 (m, 1H), 3.61-3.58 (m, 1H), 3.10-3.03 (m, 1H), 2.42-2.35 (m, 1H), 1.04 (t, 3H).

The compound F can be prepared under the reaction conditions shown in table 8 according to the procedure described in step 2 of Example 5.

TABLE 8 The reaction conditions for preparation of compound F

            No.             R³

    The mole ratio of Lithium to compound E; the amount of compound E           Reaction solvent         Reaction temperature (° C.)           Reaction time(h)           Product character         Quality; yield(%) of product F1 ethyl

5; 6.68 g ethanol 78 2 yellow solid 3.95 g; 68 F2 ethyl

5; 6.68 g ethanol 78 2 yellow solid 3.8 g; 65 F3 ethyl

5; 6.68 g ethanol 78 2 yellow solid 3.43 g; 59 F4 ethyl

5; 6.68 g ethanol 78 2 yellow solid 3.31 g; 57 F5 ethyl

5; 6.54 g ethanol 78 12 yellow solid 4.37 g; 77 F6 ethyl

5; 6.82 g ethanol 78 2 yellow solid 3.22 g; 54 F7 ethyl

5; 6.6 g ethanol 78 12 yellow solid 3.33 g; 58 F8 ethyl

5; 6.87 g ethanol 78 2 yellow solid 2.94 g; 49 F9 ethyl

5; 6.87 g ethanol 78 2 yellow solid 2.83 g; 47 F10 methyl

2; 6.39 g methanol 64 18 yellow solid 3.88 g; 72 F11 methyl

5; 6.68 g methanol 64 6 yellow solid 3.75 g; 66 F12 methyl

5; 6.68 g methanol 64 4 yellow solid 3.57 g; 63 F13 methyl

5; 6.68 g methanol 64 6 yellow solid 2.95 g; 52 F14 methyl

5; 6.68 g methanol 64 8 yellow solid 2.84 g; 50 F15 methyl

5; 6.54 g methanol 64 18 yellow solid 4.04 g; 73 F16 methyl

5; 6.82 g methanol 64 5 yellow solid 2.85 g; 49 F17 methyl

5; 6.6 g methanol 64 12 yellow solid 2.91 g; 52 F18 methyl

5; 6.87 g methanol 64 6 yellow solid 2.82 g; 48 F19 methyl

5; 6.87 g methanol 64 6 yellow solid 2.64 g; 45

TABLE 8-1 The NMR and MS datum of compound F No. ¹H NMR MS F1 ¹H NMR (400 MHz, DMSO-d₆): δ 12.06 (s, 1H), 9.65 (s, 1H), 8.02 (d, 1H), MS (ESI, pos. ion) 7.94 (d, 1H), 7.57 (dd, 1H), 7.39 (dd, 1H), 7.22 (td, 1H), 6.03 (s, 1H), m/z: 581.2 [M + H]⁺ 3.96 (q, 2H), 3.89-3.85 (m, 3H), 3.61-3.47 (m, 2H), 2.81-2.75 (m, 2H), 2.38-2.21 (m, 3H), 2.04-2.02 (m, 1H), 1.65-1.60 (m, 2H), 1.06 (t, 3H). F2 ¹H NMR (400 MHz, DMSO-d₆): δ 12.06 (s, 1H), 9.66 (s, 1H), 8.02 (d, 1H), MS (ESI, pos. ion) 7.95 (d, 1H), 7.56 (dd, 1H), 7.41 (dd, 1H), 7.20 (td, 1H), 6.03 (s, 1H), m/z: 580.9 [M + H]⁺ 3.97 (q, 2H), 3.93-3.83 (m, 3H), 3.57-3.46 (m, 2H), 2.88 (d, 1H), 2.63 (d, 1H), 2.37-2.22 (m, 3H), 2.13-2.08 (m, 1H), 1.75-1.65 (m, 2H), 1.06 (t, 3H). F3 ¹H NMR (400 MHz, DMSO-d₆): δ 12.09 (s, 1H), 9.83 (s, 1H), 8.03 (d, 1H), MS (ESI, pos. ion) 7.94 (d, 1H), 7.56 (dd, 1H), 7.40 (dd, 1H), 7.21 (td, 1H), 6.03 (s, 1H), m/z: 581.2 [M + H]⁺ 4.22 (d, 1H), 3.97 (q, 2H), 3.89 (d, 1H), 3.79-3.71 (m, 2H), 3.64-3.60 (m, 1H), 3.41 (dd, 1H), 2.88-2.83 (m, 1H), 2.57-2.52 (m, 1H), 2.47-2.44 (m, 1H), 2.38-2.18 (m, 2H), 1.80-1.73 (m, 1H), 1.64-1.54 (m, 1H), 1.06 (t, 3H). F4 ¹H NMR (400 MHz, DMSO-d₆): δ 12.14 (br, 1H), 9.82 (s, 1H), 8.02 (d, 1H), MS (ESI, pos. ion) 7.92 (d, 1H), 7.54 (dd, 1H), 7.40 (dd, 1H), 7.22 (td, 1H), 6.03 (s, 1H), m/z: 580.9 [M + H]+ 4.18 (d, 1H), 3.96 (q, 2H), 3.91 (d, 1H), 3.82-3.79 (m, 1H), 3.74-3.71 (m, 1H), 3.61-3.57 (m, 1H), 3.37-3.32 (m, 1H), 2.78-2.75 (m, 1H), 2.57-2.53 (m, 1H), 2.49-2.47 (m, 1H), 2.38-2.32 (m, 2H), 1.89-1.84 (m, 1H), 1.68-1.58 (m, 1H), 1.06 (t, 3H). F5 ¹H NMR (400 MHz, DMSO-d₆): δ 13.02 (s, 1H), 9.78 (s, 1H), 8.03 (d, 1H), MS (ESI, pos. ion) 7.93 (d, 1H), 7.56 (dd, 1H), 7.39 (dd, 1H), 7.22 (td, 1H), 6.00 (s, 1H), m/z: 567.1 [M + H]⁺ 4.10 (d, 1H), 3.95 (q, 2H), 3.90-3.87 (m, 1H), 3.76-3.60 (m, 3H), 3.46-3.42 (m, 1H), 2.98 (d, 1H), 2.93 (d, 1H), 1.21 (d, 3H), 1.05 (t, 3H). F6 ¹H NMR (400 MHz, DMSO-d₆): δ 12.11 (s, 1H), 9.74 (s, 1H), 8.02 (d, 1H), MS (ESI, pos. ion) 7.95 (d, 1H), 7.56 (dd, 1H), 7.39 (dd, 1H), 7.19 (td, 1H), 6.04 (s, 1H), m/z: 594.6 [M + H]⁺ 4.16 (d, 1H), 4.00-3.93 (m, 2H), 3.86 (d, 1H), 3.77-3.72 (m, 1H), 3.59-3.53 (m, 1H), 3.51-3.45 (m, 1H), 2.66 (d, 1H), 2.46-2.40 (m, 1H), 2.37-2.30 (m, 3H), 2.03-1.91 (m, 1H), 1.80-1.73 (m, 1H), 1.20 (d, 3H), 1.06 (t, 3H). F7 ¹H NMR (600 MHz, DMSO-d₆): δ 9.98 (br, 1H), 8.03 (d, 1H), 8.00 (d, 1H), MS (ESI, pos. ion) 7.61 (dd, 1H), 7.48 (dd, 1H), 7.28 (td, 1H), 6.02 (s, 1H), 4.35 (d, 1H), m/z: 573.0 [M + H]⁺ 4.13 (d, 1H), 4.01-3.94 (m, 3H), 3.61-3.51 (m, 1H), 3.25-3.19 (m, 1H), 3.10-3.04 (m, 1H), 2.86-2.68 (m, 1H), 1.20 (t, 3H). F8 ¹H NMR (600 MHz, DMSO-d₆): δ 12.08 (s, 1H), 9.51 (s, 1H), 8.01 (d, 1H), MS (ESI, pos. ion) 7.93 (d, 1H), 7.57 (dd, 1H), 7.41 (dd, 1H), 7.24 (td, 1H), 6.01 (s, 1H), m/z: 601.1 [M + H]⁺ 4.12 (dd, 2H), 3.97 (q, 2H), 3.61-3.52 (m, 1H), 3.04-2.96 (m, 2H), 2.58-2.56 (m, 1H), 2.35-2.20 (m, 2H), 2.12-1.98 (m, 1H), 1.93-1.90 (m, 1H), 1.56-1.48 (m, 1H), 1.06 (t, 3H). F9 ¹H NMR (400 MHz, CDCl₃): δ 12.19 (br, 1H), 9.46 (s, 1H), 7.86 (d, 1H), MS (ESI, pos. ion) 7.50 (d, 1H), 7.37-7.33 (m, 2H), 7.00 (td, 1H), 6.19 (s, 1H), 4.52 (d, 1H), m/z: 601.2 [M + H]⁺ 4.14-4.03 (m, 2H), 3.65 (d, 1H), 3.31-3.23 (m, 2H), 3.02-2.91 (m, 1H), 2.57-2.25 (m, 5H), 1.79-1.74 (m, 1H), 1.16 (t, 3H). F10 ¹H NMR (600 MHz, DMSO-d₆): δ 12.88 (br, 1H), 10.07 (br, 1H), 8.02 (d, 1H), MS (ESI, pos. ion) 7.93 (d, 1H), 7.56 (dd, 1H), 7.39 (dd, 1H), 7.23 (td, 1H), 6.01 (s, 1H), m/z: 539.1 [M + H]⁺ 4.25 (d, 1H), 4.04 (d, 1H), 3.99 (dd, 1H), 3.84 (dd, 1H), 3.73-3.70 (m, 1H), 3.69-3.65 (m, 1H), 3.62-3.58 (m, 1H), 3.5 (s, 3H), 3.10-3.07 (m, 1H), 2.41-2.39 (m, 1H). F11 ¹H NMR (400 MHz, DMSO-d₆): δ 12.03 (s, 1H), 9.69 (s, 1H), 8.01 (d, 1H), MS (ESI, pos. ion) 7.93 (d, 1H), 7.56 (dd, 1H), 7.38 (dd, 1H), 7.23 (td, 1H), 6.01 (s, 1H), m/z: 567.2 [M + H]⁺ 3.93-3.83 (m, 3H), 3.60-3.53 (m, 2H), 3.52 (s, 3H), 2.77 (dd, 2H), 2.38-2.25 (m, 3H), 2.05-1.99 (m, 1H), 1.65-1.59 (m, 2H). F12 ¹H NMR (600 MHz, DMSO-d₆): δ 12.06 (s, 1H), 9.70 (s, 1H), 8.03 (d, 1H), MS (ESI, pos. ion) 7.94 (d, 1H), 7.57 (dd, 1H), 7.39 (dd, 1H), 7.23 (td, 1H), 6.02 (s, 1H), m/z: 567.2 [M + H]⁺ 3.95 (d, 1H), 3.86-3.80 (m, 2H), 3.56-3.54 (m, 1H), 3.53 (s, 3H), 3.52-3.49 (m, 1H), 2.88 (d, 1H), 2.62 (d, 1H), 2.37-2.21 (m, 3H), 2.15-2.08 (m, 1H), 1.72-1.64 (m, 2H). F13 ¹H NMR (400 MHz, DMSO-d₆): δ 12.06 (s, 1H), 9.81 (s, 1H), 8.01 (d, 1H), MS (ESI, pos. ion) 7.96 (d, 1H), 7.54 (dd, 1H), 7.41 (dd, 1H), 7.23 (td, 1H), 6.02 (s, 1H), m/z: 567.1 [M + H]⁺ 4.24 (d, 1H), 3.90 (d, 1H), 3.78-3.70 (m, 2H), 3.65-3.61 (m, 1H), 3.52 (s, 3H), 3.42 (dd, 1H), 2.89-2.83 (m, 1H), 2.58-2.53 (m, 1H), 2.48-2.43 (m, 1H), 2.37-2.17 (m, 2H), 1.81-1.72 (m, 1H), 1.65-1.55 (m, 1H). F14 ¹H NMR (400 MHz, DMSO-d₆): δ 9.87 (s, 1H), 8.03 (d, 1H), 7.94 (d, 1H), MS (ESI, pos. ion) 7.56 (dd, 1H), 7.38 (dd, 1H), 7.23 (td, 1H), 6.01 (s, 1H), 4.18 (d, 1H), 3.91 (d, 1H), m/z: 567.2 [M + H]⁺ 3.83-3.79 (m, 1H), 3.75-3.70 (m, 1H), 3.61-3.56 (m, 1H), 3.53 (s, 3H), 3.47-3.40 (m, 1H), 3.04-2.86 (m, 1H), 2.77-2.75 (m, 1H), 2.58-2.54 (m, 1H), 2.37-2.22 (m, 2H), 1.88-1.84 (m, 1H), 1.65-1.58 (m, 1H). F15 ¹H NMR (400 MHz, DMSO-d₆): δ 13.02 (s, 1H), 9.83 (s, 1H), 8.02 (d, 1H), MS (ESI, pos. ion) 7.94 (d, 1H), 7.56 (dd, 1H), 7.38 (dd, 1H), 7.22 (td, 1H), 5.99 (s, 1H), m/z: 553.0 [M + H]⁺ 4.05 (d, 1H), 3.90-3.85 (m, 1H), 3.75-3.60 (m, 3H), 3.52 (s, 3H), 3.47-3.42 (m, 1H), 3.00 (d, 1H), 2.92 (d, 1H), 1.21 (d, 3H). F16 ¹H NMR (400 MHz, DMSO-d₆): δ 12.10 (s, 1H), 9.75 (s, 1H), 8.01 (d, 1H), MS (ESI, pos. ion) 7.96 (d, 1H), 7.54 (dd, 1H), 7.40 (dd, 1H), 7.20 (td, 1H), 6.02 (s, 1H), m/z: 581.2 [M + H]⁺ 4.18 (d, 1H), 3.88 (d, 1H), 3.78-3.73 (m, 1H), 3.60-3.54 (m, 1H), 3.52 (s, 3H), 3.50-3.45 (m, 1H), 2.68 (d, 1H), 2.47-2.41 (m, 1H), 2.36-2.30 (m, 3H), 2.04-1.92 (m, 1H), 1.81-1.73 (m, 1H), 1.21 (d, 3H). F17 ¹H NMR (600 MHz, DMSO-d₆): δ 9.71 (br, 1H), 7.98 (d, 1H), 7.91 (d, 1H), MS (ESI, pos. ion) 7.56 (dd, 1H), 7.40 (dd, 1H), 7.23 (td, 1H), 5.99 (s, 1H), 4.33 (d, 1H), m/z: 558.6 [M + H]⁺ 4.09 (d, 1H), 3.93-3.88 (m, 1H), 3.52 (s, 3H), 3.49-3.45 (m, 1H), 3.22-3.08 (m, 2H), 2.82-2.74 (m, 1H). F18 ¹H NMR (400 MHz, DMSO-d₆): δ 11.03 (s, 1H), 9.57 (s, 1H), 7.99 (d, 1H), MS (ESI, pos. ion) 7.92 (d, 1H), 7.55 (dd, 1H), 7.39 (dd, 1H), 7.23 (td, 1H), 6.00 (s, 1H), m/z: 587.2 [M + H]⁺ 4.14 (dd, 2H), 3.62-3.54 (m, 1H), 3.53 (s, 3H), 3.05-2.96 (m, 2H), 2.57-2.56 (m, 1H), 2.36-2.20 (m, 2H), 2.13-1.98 (m, 1H), 1.95-1.90 (m, 1H), 1.56-1.46 (m, 1H). F19 ¹H NMR (400 MHz, CDCl₃): δ 12.15 (br, 1H), 9.47 (s, 1H), 7.85 (d, 1H), MS (ESI, pos. ion) 7.51 (d, 1H), 7.38-7.33 (m, 2H), 7.01 (td, 1H), 6.17 (s, 1H), 4.50 (d, 1H), 3.66 (d, 1H), m/z: 587.2 [M + H]⁺ 3.55 (s, 3H), 3.33-3.23 (m, 2H), 3.04-2.92 (m, 1H), 2.58-2.25 (m, 5H), 1.78-1.74 (m, 1H).

Example 6 The Preparation of (R)-ethyl 4-(2-bromo-4-fluorophenyl)-6-(morpholinomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate

Step 1) (R)-ethyl 4-(2-bromo-4-fluorophenyl)-6-methyl-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate

To a flask were added anhydrous ethanol (446 g) and lithium (2.43 g, 0.35 mol) in turn. The mixture was stirred at 43° C. until the lithium was consumed entirely, and then a solution of (R)—(S)-1-isopropoxy-1-oxopropan-2-yl 4-(2-bromo-4-fluorophenyl)-6-methyl-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (51 g, 0.1 mol) in ethanol (446 g) was added. The reaction mixture was allowed to warm up to 78° C. and stirred for 1.5 hours under nitrogen atmosphere. After the reaction, the reaction mixture was cooled to 10° C., kept at 10° C. and stirred for 8 hours. The mixture was filtered. The filtrate was washed with anhydrous ethanol (51 g) and water (510 g) in turn, and then dried in vacuo at 60° C. for 8 hours to obtain the product as a yellow solid (29.7 g, 70%).

[a]_(D) ²⁵=−80.71 (c=0.3023 g/100 mL, MeOH);

MS (ESI, pos.ion) m/z: 424.0 [M+H]⁺;

¹H NMR (400 MHz, DMSO-d₆): δ 9.88 (s, 1H), 7.97 (d, 1H), 7.89 (d, 1H), 7.54 (dd, 1H), 7.35 (dd, 1H), 7.23 (td, 1H), 5.96 (s, 1H), 3.93 (q, 2H), 2.46 (s, 3H), 1.03 (t, 3H).

The compound G can be prepared under the reaction conditions shown in table 9 according to the procedure described in step 1 of Example 6.

TABLE 9 The reaction conditions for preparation of compound G

The mole ratio of Lithium to compound (5); The mass ratio Quality; the amount of of reaction Reaction yield(%) compound (5) Reaction solvent to temperature Reaction Product of No. R³ is 51 g solvent compound (5); (° C.) time (h) character product G1 ethyl 2.5 ethanol 10 78 12 yellow 20.8 g; 49 solid G1 ethyl 3 ethanol 6 78 8 yellow 31.8 g; 75 solid G1 ethyl 4 ethanol 10 78 4 yellow 31.4 g; 74 solid G1 ethyl 5 ethanol 20 78 24 yellow 32.2 g; 76 solid G1 ethyl 6 ethanol 30 78 12 yellow 27.6 g; 65 solid G1 ethyl 8 ethanol 20 78 12 yellow 29.7 g; 70 solid G2 methyl 2.5 methanol 4 64 20 yellow 20.9 g; 51 solid G2 methyl 3 methanol 6 64 6 yellow 23 g; 56 solid G2 methyl 4 methanol 8 64 8 yellow 21.3 g; 52 solid G2 methyl 3 methanol 10 64 10 yellow 20.5 g; 50 solid G2 methyl 3 methanol 20 64 3 yellow 16.4 g; 40 solid

TABLE 9-1 The NMR, MS and specific rotation datum of the compound G No. ¹H NMR MS specific rotation G1 ¹H NMR (400 MHz, DMSO-d₆): δ 9.88 (s, 1H), MS (ESI, pos. ion) [a]_(D) ²⁵ = −80.71 (c = 7.97 (d, 1H), 7.89 (d, 1H), 7.54 (dd, 1H), 7.35 (dd, 1H), m/z: 424.0 [M + H]⁺ 0.3023 g/100 mL, 7.23 (td, 1H), 5.96 (s, 1H), 3.93 (q, 2H), 2.46 (s, 3H), MeOH) 1.03 (t, 3H). G2 ¹H NMR (400 MHz, DMSO-d₆): δ 7.79 (d, 1H), MS (ESI, pos. ion) [a]_(D) ²⁵ = −86.04 (c = 7.67 (d, 1H), 7.42 (dd, 2H), 7.36 (dd, 1H), 7.15 (td, 1H), m/z: 410.0 [M + H]⁺ 0.3022 g/100 mL, 5.85 (s, 1H), 3.40 (s, 3H), 2.33 (s, 3H). MeOH)

Step 2) (R)-ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate

To a flask were added (R)-ethyl 4-(2-bromo-4-fluorophenyl)-6-methyl-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (42.4 g, 0.1 mol) and CCl₄ (800 mL), followed by NBS (19.6 g, 0.11 mol) at 70° C. The mixture was stirred for 30 min. After the reaction, the mixture was cooled and filtered. The filtrate was concentrated to obtain the product as a yellow solid (34.2 g, 68%).

MS (ESI, pos.ion) m/z: 503.9 [M+H];

¹H NMR (600 MHz, DMSO-d₆): δ 10.23 (s, 1H), 8.01 (d, 1H), 7.98 (d, 1H), 7.62 (dd, 1H), 7.42 (dd, 1H), 7.29 (td, 1H), 6.01 (s, 1H), 4.79 (br, 2H), 4.01 (q, 2H), 1.08 (t, 3H).

The compound J can be prepared under the reaction conditions shown in table 10 according to the procedure described in step 2 of Example 6.

TABLE 10 The reaction conditions for preparation of compound J

The mole ratio of NBS to The mass ratio Quality; compound (G); of reaction Reaction yield(%) the amount of Reaction solvent to temperature Product of No. R³ compound (G) solvent compound (G); (° C.) character product J1 ethyl 1.0; DCM 10 39 yellow 35.2 g; 42.4 g solid 70 J1 ethyl 1.0; CHCl₃ 20 61 yellow 36.3 g; 42.4 g solid 72 J1 ethyl 1.1; CCl₄ 30 76 yellow 44.3 g; 42.4 g solid 88 J2 methyl 1.0; DCM 10 39 yellow 29.9 g; 41 g solid 73 J2 methyl 1.1; CHCl₃ 20 61 yellow 30.8 g; 41 g solid 75 J2 methyl 1.1; CCl₄ 30 76 yellow 34.9 g; 41 g solid 85

TABLE 10-1 The NMR and MS datum of the compound J No. ¹H NMR MS J1 ¹H NMR (600 MHz, DMSO-d₆): δ 10.23 (s, 1H), 8.01 (d, 1H), 7.98 (d, 1H), MS (ESI, pos. ion) 7.62 (dd, 1H), 7.42 (dd, 1H), 7.29 (td, 1H), 6.01 (s, 1H), 4.79 (br, 2H), m/z: 503.9 [M + H]⁺ 4.01 (q, 2H), 1.08 (t, 3H). J2 ¹H NMR (400 MHz, CDCl₃): δ 8.87 (d, 1H), 7.54 (d, 1H), 7.40 (dd, 1H), MS (ESI, pos. ion) 7.35 (dd, 1H), 7.03 (td, 1H), 6.11 (s, 1H), 4.97 (d, 1H), 4.64 (d, 1H), 3.69 (s, m/z: 489.9 [M + H]⁺ 3H).

Step 3) (R)-ethyl 4-(2-bromo-4-fluorophenyl)-6-(morpholinomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate

To a flask were added (R)-ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (50.3 g, 0.1 mol), anhydrous ethanol (302 g) and morpholine (34.8 g, 0.4 mol). The mixture was stirred at 25° C. under nitrogen atmosphere for 6 hours. After the reaction, the mixture was concentrated. To the residue was added ethyl acetate (500 g), the resulting mixture was washed with water (250 mL×2). The organic layer was concentrated to give the product as tawny oil (37.3 g, 74%)

MS (ESI, pos.ion) m/z: 509.1 [M+H];

¹H NMR (600 MHz, DMSO-d₆): δ 9.69 (s, 1H), 8.02 (d, 1H), 7.93 (d, 1H), 7.57 (dd, 1H), 7.40 (dd, 1H), 7.22 (td, 1H), 6.05 (s, 1H), 3.96 (q, 4H), 3.93 (dd, 2H), 3.68 (br, 4H), 2.56 (br, 4H), 1.05 (t, 3H).

The compound L can be prepared under the reaction conditions shown in table 11 according to the procedure described in step 3 of Example 6.

TABLE 11 The reaction conditions for preparation of compound L

The mole ratio of compound (6) to compound (J); The mass ratio of Reaction Quality; the amount of Reaction reaction solvent temperature Reaction Product yield(%) No. R³ compound (J) solvent to compound (J); (° C.) time(h) character of product L1 ethyl 2; 50.3 g ethanol 20 25 2 tawny 38.2 g; oil 75 L1 ethyl 3; 50.3 g acetone 10 40 10 tawny 40.8 g; oil 80 L1 ethyl 4; 50.3 g methanol 10 30 6 tawny 38.7 g; oil 76 L1 ethyl 5; 50.3 g ethyl 20 50 24 tawny 35.7 g; acetate oil 70 L1 ethyl 6; 50.3 g DCM 8 39 6 tawny 36.2 g; oil 71 L1 ethyl 3; 50.3 g DMF 4 60 1 tawny 36.7 g; oil 72 L1 ethyl 4; 50.3 g THF 6 50 8 tawny 38.2 g; oil 75 L2 methyl 2; 48.9 g ethanol 20 25 2 tawny 36.2 g; oil 73 L2 methyl 3; 48.9 g acetone 10 40 10 tawny 37.6 g; oil 76 L2 methyl 4; 48.9 g methanol 10 30 6 tawny 39.6 g; oil 80 L2 methyl 5; 48.9 g ethyl 20 50 24 tawny 38.6 g; acetate oil 78 L2 methyl 6; 48.9 g DCM 8 39 6 tawny 35.2 g; oil 71 L2 methyl 3; 48.9 g DMF 4 60 1 tawny 36.2 g; oil 73 L2 methyl 4; 48.9 g THF 6 50 8 tawny 35.7 g; oil 72

TABLE 11-1 The NMR and MS datum of the compound L No. ¹H NMR MS L1 ¹H NMR (600 MHz, DMSO-d₆): δ 9.69 (s, 1H), 8.02 (d, 1H), 7.93 (d, 1H), MS (ESI, pos. ion) m/z: 7.57 (dd, 1H), 7.40 (dd, 1H), 7.22 (td, 1H), 6.05 (s, 1H), 3.96 (q, 4H), 509.1 [M + H]⁺ 3.93 (dd, 2H), 3.68 (br, 4H), 2.56 (br, 4H), 1.05 (t, 3H). L2 ¹H NMR (600 MHz, DMSO-d₆): δ 9.71 (s, 1H), 8.02 (d, 1H), 7.94 (d, 1H), MS (ESI, pos. ion) m/z: 7.55 (dd, 1H), 7.37 (dd, 1H), 7.20 (td, 1H), 6.02 (s, 1H), 3.91 (dd, 2H), 494.7 [M + H]⁺ 3.67 (br, 4H), 3.52 (s, 3H), 2.55 (br, 4H).

Example 7 The Preparation of (S)-4-(((R)-6-(2-bromo-4-fluorophenyl)-5-(ethoxycarbonyl)-2-(thiazol-2-yl)-3,6-dihydropyrimidin-4-yl)methyl)morpholine-3-carboxylic acid

To a flask were added (R)-ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (5.03 g, 10 mmol), (S)-morpholine-3-carboxylic acid (1.31 g, 10 mmol), potassium carbonate (2.76 g, 20 mmol) and ethanol (100 mL). The mixture was stirred at 30° C. under nitrogen atmosphere for 12 hours. After the reaction, the mixture was filtered. The filtrate was concentrated. To the residue was added water (100 mL). The resulting mixture was extracted with ethyl acetate (100 mL). The organic phase was abandoned. To the aqueous layer was added ethyl acetate (100 mL), the mixture was adjusted to pH 3-6 with concentrated hydrochloric acid. After partitioned, the organic layer was dried over anhydrous sodium sulfate and concentrated to give the product as a yellow solid (4.4 g, 80%).

MS (ESI, pos.ion) m/z: 553.2[M+H]⁺;

¹H NMR (400 MHz, DMSO-d₆): δ 12.85 (br, 1H), 9.80 (s, 1H), 8.00 (d, 1H), 7.91 (d, 1H), 7.54 (dd, 1H), 7.39 (dd, 1H), 7.19 (td, 1H), 6.01 (s, 1H), 4.25 (d, 1H), 4.02 (d, 1H), 3.97-3.91 (m, 3H), 3.81 (dd, 1H), 3.72-3.69 (m, 1H), 3.66-3.63 (m, 1H), 3.61-3.58 (m, 1H), 3.10-3.03 (m, 1H), 2.42-2.35 (m, 1H), 1.04 (t, 3H).

The compound F can be prepared under the reaction conditions shown in table 12 according to the procedure described in Example 7.

TABLE 12 The reaction conditions for preparation of compound F

                  No.                   R³

      The mole ratio of compound (J) to compound (VI); the amount of compound (J)                 Reaction solvent         The mass ratio of reaction solvent to compound (J);               Reaction temperature (° C.)                 Reaction time(h)                 Product character             Quality; yield(%) of product F1 ethyl

1; 5.03 g ethanol 8 30 4 yellow solid 4.07 g; 70 F2 ethyl

1; 5.03 g ethanol 4 30 8 yellow solid 4.12 g; 71 F3 ethyl

1; 5.03 g ethanol 10 30 12 yellow solid 2.79 g; 48 F4 ethyl

1; 5.03 g ethanol 20 30 24 yellow solid 2.61 g; 45 F5 ethyl

1; 5.03 g ethanol 30 30 6 yellow solid 4.54 g; 80 F6 ethyl

1; 5.03 g ethanol 15 30 24 yellow solid 3.04 g; 51 F7 ethyl

1; 5.03 g ethanol 20 30 6 yellow solid 4.47 g; 78 F8 ethyl

1; 5.03 g ethanol 25 30 12 yellow solid 3.91 g; 65 F9 ethyl

1; 5.03 g ethanol 14 30 12 yellow solid 4.09 g; 68 F10 methyl

1; 4.89 g ethanol 8 30 4 yellow solid 3.83 g; 71 F11 methyl

1; 4.89 g ethanol 4 30 8 yellow solid 3.85 g; 68 F12 methyl

1; 4.89 g ethanol 10 30 12 yellow solid 3.74 g; 66 F13 methyl

1; 4.89 g ethanol 20 30 24 yellow solid 2.55 g; 45 F14 methyl

1; 4.89 g ethanol 30 30 6 yellow solid 2.50 g; 44 F15 methyl

1; 4.89 g ethanol 8 30 12 yellow solid 4.32 g; 78 F16 methyl

1; 4.89 g ethanol 20 30 6 yellow solid 2.79 g; 48 F17 methyl

1; 4.89 g ethanol 25 30 12 yellow solid 4.14 g; 74 F18 methyl

1; 4.89 g ethanol 14 30 12 yellow solid 3.64 g; 62 F19 methyl

1; 4.89 g ethanol 15 30 24 yellow solid 3.7 g; 63

TABLE 12-1 The NMR and MS datum of the compound F No. ¹H NMR MS F1 ¹H NMR (400 MHz, DMSO-d₆): δ 12.06 (s, 1H), 9.65 (s, 1H), 8.02 (d, 1H), MS (ESI, pos. ion) 7.94 (d, 1H), 7.57 (dd, 1H), 7.39 (dd, 1H), 7.22 (td, 1H), 6.03 (s, 1H), m/z: 581.2 [M + H]⁺ 3.96 (q, 2H), 3.89-3.85 (m, 3H), 3.61-3.47 (m, 2H), 2.81-2.75 (m, 2H), 2.38-2.21 (m, 3H), 2.04-2.02 (m, 1H), 1.65-1.60 (m, 2H), 1.06 (t, 3H). F2 ¹H NMR (400 MHz, DMSO-d₆): δ 12.06 (s, 1H), 9.66 (s, 1H), 8.02 (d, 1H), MS (ESI, pos. ion) 7.95 (d, 1H), 7.56 (dd, 1H), 7.41 (dd, 1H), 7.20 (td, 1H), 6.03 (s, 1H), m/z: 580.9 [M + H]⁺ 3.97 (q, 2H), 3.93-3.83 (m, 3H), 3.57-3.46 (m, 2H), 2.88 (d, 1H), 2.63 (d, 1H), 2.37-2.22 (m, 3H), 2.13-2.08 (m, 1H), 1.75-1.65 (m, 2H), 1.06 (t, 3H). F3 ¹H NMR (400 MHz, DMSO-d₆): δ 12.09 (s, 1H), 9.83 (s, 1H), 8.03 (d, 1H), MS (ESI, pos. ion) 7.94 (d, 1H), 7.56 (dd, 1H), 7.40 (dd, 1H), 7.21 (td, 1H), 6.03 (s, 1H), m/z: 581.2 [M + H]⁺ 4.22 (d, 1H), 3.97 (q, 2H), 3.89 (d, 1H), 3.79-3.71 (m, 2H), 3.64-3.60 (m, 1H), 3.41 (dd, 1H), 2.88-2.83 (m, 1H), 2.57-2.52 (m, 1H), 2.47-2.44 (m, 1H), 2.38-2.18 (m, 2H), 1.80-1.73 (m, 1H), 1.64-1.54 (m, 1H), 1.06 (t, 3H). F4 ¹H NMR (400 MHz, DMSO-d₆): δ 12.14 (br, 1H), 9.82 (s, 1H), 8.02 (d, 1H), MS (ESI, pos. ion) 7.92 (d, 1H), 7.54 (dd, 1H), 7.40 (dd, 1H), 7.22 (td, 1H), 6.03 (s, 1H), m/z: 580.9 [M + H]⁺ 4.18 (d, 1H), 3.96 (q, 2H), 3.91 (d, 1H), 3.82-3.79 (m, 1H), 3.74-3.71 (m, 1H), 3.61-3.57 (m, 1H), 3.37-3.32 (m, 1H), 2.78-2.75 (m, 1H), 2.57-2.53 (m, 1H), 2.49-2.47 (m, 1H), 2.38-2.32 (m, 2H), 1.89-1.84 (m, 1H), 1.68-1.58 (m, 1H), 1.06 (t, 3H). F5 ¹H NMR (400 MHz, DMSO-d₆): δ 13.02 (s, 1H), 9.78 (s, 1H), 8.03 (d, 1H), MS (ESI, pos. ion) 7.93 (d, 1H), 7.56 (dd, 1H), 7.39 (dd, 1H), 7.22 (td, 1H), 6.00 (s, 1H), m/z: 567.1 [M + H]⁺ 4.10 (d, 1H), 3.95 (q, 2H), 3.90-3.87 (m, 1H), 3.76-3.60 (m, 3H), 3.46-3.42 (m, 1H), 2.98 (d, 1H), 2.93 (d, 1H), 1.21 (d, 3H), 1.05 (t, 3H). F6 ¹H NMR (400 MHz, DMSO-d₆): δ 12.11 (s, 1H), 9.74 (s, 1H), 8.02 (d, 1H), MS (ESI, pos. ion) 7.95 (d, 1H), 7.56 (dd, 1H), 7.39 (dd, 1H), 7.19 (td, 1H), 6.04 (s, 1H), m/z: 594.6 [M + H]⁺ 4.16 (d, 1H), 4.00-3.93 (m, 2H), 3.86 (d, 1H), 3.77-3.72 (m, 1H), 3.59-3.53 (m, 1H), 3.51-3.45 (m, 1H), 2.66 (d, 1H), 2.46-2.40 (m, 1H), 2.37-2.30 (m, 3H), 2.03-1.91 (m, 1H), 1.80-1.73 (m, 1H), 1.20 (d, 3H), 1.06 (t, 3H). F7 ¹H NMR (600 MHz, DMSO-d₆): δ 9.98 (br, 1H), 8.03 (d, 1H), 8.00 (d, 1H), MS (ESI, pos. ion) 7.61 (dd, 1H), 7.48 (dd, 1H), 7.28 (td, 1H), 6.02 (s, 1H), 4.35 (d, 1H), m/z: 573.0 [M + H]⁺ 4.13 (d, 1H), 4.01-3.94 (m, 3H), 3.61-3.51 (m, 1H), 3.25-3.19 (m, 1H), 3.10-3.04 (m, 1H), 2.86-2.68 (m, 1H), 1.20 (t, 3H). F8 ¹H NMR (600 MHz, DMSO-d₆): δ 12.08 (s, 1H), 9.51 (s, 1H), 8.01 (d, 1H), MS (ESI, pos. ion) 7.93 (d, 1H), 7.57 (dd, 1H), 7.41 (dd, 1H), 7.24 (td, 1H), 6.01 (s, 1H), m/z: 601.1 [M + H]⁺ 4.12 (dd, 2H), 3.97 (q, 2H), 3.61-3.52 (m, 1H), 3.04-2.96 (m, 2H), 2.58-2.56 (m, 1H), 2.35-2.20 (m, 2H), 2.12-1.98 (m, 1H), 1.93-1.90 (m, 1H), 1.56-1.48 (m, 1H), 1.06 (t, 3H). F9 ¹H NMR (400 MHz, CDCl₃): δ 12.19 (br, 1H), 9.46 (s, 1H), 7.86 (d, 1H), MS (ESI, pos. ion) 7.50 (d, 1H), 7.37-7.33 (m, 2H), 7.00 (td, 1H), 6.19 (s, 1H), 4.52 (d, 1H), m/z: 601.2 [M + H]⁺ 4.14-4.03 (m, 2H), 3.65 (d, 1H), 3.31-3.23 (m, 2H), 3.02-2.91 (m, 1H), 2.57-2.25 (m, 5H), 1.79-1.74 (m, 1H), 1.16 (t, 3H). F10 ¹H NMR (600 MHz, DMSO-d₆): δ 12.88 (br, 1H), 10.07 (br, 1H), 8.02 (d, 1H), MS (ESI, pos. ion) 7.93 (d, 1H), 7.56 (dd, 1H), 7.39 (dd, 1H), 7.23 (td, 1H), 6.01 (s, 1H), m/z: 539.1 [M + H]⁺ 4.25 (d, 1H), 4.04 (d, 1H), 3.99 (dd, 1H), 3.84 (dd, 1H), 3.73-3.70 (m, 1H), 3.69-3.65 (m, 1H), 3.62-3.58 (m, 1H), 3.51 (s, 3H), 3.10-3.07 (m, 1H), 2.41-2.39 (m, 1H). F11 ¹H NMR (400 MHz, DMSO-d₆): δ 12.03 (s, 1H), 9.69 (s, 1H), 8.01 (d, 1H), MS (ESI, pos. ion) 7.93 (d, 1H), 7.56 (dd, 1H), 7.38 (dd, 1H), 7.23 (td, 1H), 6.01 (s, 1H), m/z: 567.2 [M + H]⁺ 3.93-3.83 (m, 3H), 3.60-3.53 (m, 2H), 3.52 (s, 3H), 2.77 (dd, 2H), 2.38-2.25 (m, 3H), 2.05-1.99 (m, 1H), 1.65-1.59 (m, 2H). F12 ¹H NMR (600 MHz, DMSO-d₆): δ 12.06 (s, 1H), 9.70 (s, 1H), 8.03 (d, 1H), MS (ESI, pos. ion) 7.94 (d, 1H), 7.57 (dd, 1H), 7.39 (dd, 1H), 7.23 (td, 1H), 6.02 (s, 1H), m/z: 567.2 [M + H]⁺ 3.95 (d, 1H), 3.86-3.80 (m, 2H), 3.56-3.54 (m, 1H), 3.53 (s, 3H), 3.52-3.49 (m, 1H), 2.88 (d, 1H), 2.62 (d, 1H), 2.37-2.21 (m, 3H), 2.15-2.08 (m, 1H), 1.72-1.64 (m, 2H). F13 ¹H NMR (400 MHz, DMSO-d₆): δ 12.06 (s, 1H), 9.81 (s, 1H), 8.01 (d, 1H), MS (ESI, pos. ion) 7.96 (d, 1H), 7.54 (dd, 1H), 7.41 (dd, 1H), 7.23 (td, 1H), 6.02 (s, 1H), m/z: 567.1 [M + H]⁺ 4.24 (d, 1H), 3.90 (d, 1H), 3.78-3.70 (m, 2H), 3.65-3.61 (m, 1H), 3.52 (s, 3H), 3.42 (dd, 1H), 2.89-2.83 (m, 1H), 2.58-2.53 (m, 1H), 2.48-2.43 (m, 1H), 2.37-2.17 (m, 2H), 1.81-1.72 (m, 1H), 1.65-1.55 (m, 1H). F14 ¹H NMR (400 MHz, DMSO-d₆): δ 9.87 (s, 1H), 8.03 (d, 1H), 7.94 (d, 1H), MS (ESI, pos. ion) 7.56 (dd, 1H), 7.38 (dd, 1H), 7.23 (td, 1H), 6.01 (s, 1H), 4.18 (d, 1H), m/z: 567.2 [M + H]⁺ 3.91 (d, 1H), 3.83-3.79 (m, 1H), 3.75-3.70 (m, 1H), 3.61-3.56 (m, 1H), 3.53 (s, 3H), 3.47-3.40 (m, 1H), 3.04-2.86 (m, 1H), 2.77-2.75 (m, 1H), 2.58-2.54 (m, 1H), 2.37-2.22 (m, 2H), 1.88-1.84 (m, 1H), 1.65-1.58 (m, 1H). F15 ¹H NMR (400 MHz, DMSO-d₆): δ 13.02 (s, 1H), 9.83 (s, 1H), 8.02 (d, 1H), MS (ESI, pos. ion) 7.94 (d, 1H), 7.56 (dd, 1H), 7.38 (dd, 1H), 7.22 (td, 1H), 5.99 (s, 1H), m/z: 553.0 [M + H]⁺ 4.05 (d, 1H), 3.90-3.85 (m, 1H), 3.75-3.60 (m, 3H), 3.47-3.42 (m, 1H), 3.00 (d, 1H), 2.92 (d, 1H), 1.21 (d, 3H). F16 ¹H NMR (400 MHz, DMSO-d₆): δ 12.10 (s, 1H), 9.75 (s, 1H), 8.01 (d, 1H), MS (ESI, pos. ion) 7.96 (d, 1H), 7.54 (dd, 1H), 7.40 (dd, 1H), 7.20 (td, 1H), 6.02 (s, 1H), m/z: 581.2 [M + H]⁺ 4.18 (d, 1H), 3.88 (d, 1H), 3.78-3.73 (m, 1H), 3.60-3.54 (m, 1H), 3.52 (s, 3H), 3.50-3.45 (m, 1H), 2.68 (d, 1H), 2.47-2.41 (m, 1H), 2.36-2.30 (m, 3H), 2.04-1.92 (m, 1H), 1.81-1.73 (m, 1H), 1.21 (d, 3H). F17 ¹H NMR (600 MHz, DMSO-d₆): δ 9.71 (br, 1H), 7.98 (d, 1H), 7.91 (d, 1H), MS (ESI, pos. ion) 7.56 (dd, 1H), 7.40 (dd, 1H), 7.23 (td, 1H), 5.99 (s, 1H), 4.33 (d, 1H), m/z: 558.6 [M + H]⁺ 4.09 (d, 1H), 3.93-3.88 (m, 1H), 3.52 (s, 3H), 3.49-3.45 (m, 1H), 3.22-3.08 (m, 2H), 2.82-2.74 (m, 1H). F18 ¹H NMR (400 MHz, DMSO-d₆): δ 11.03 (s, 1H), 9.57 (s, 1H), 7.99 (d, 1H), MS (ESI, pos. ion) 7.92 (d, 1H), 7.55 (dd, 1H), 7.39 (dd, 1H), 7.23 (td, 1H), 6.00 (s, 1H), m/z: 587.2 [M + H]⁺ 4.14 (dd, 2H), 3.62-3.54 (m, 1H), 3.53 (s, 3H), 3.05-2.96 (m, 2H), 2.57-2.56 (m, 1H), 2.36-2.20 (m, 2H), 2.13-1.98 (m, 1H), 1.95-1.90 (m, 1H), 1.56-1.46 (m, 1H). F19 ¹H NMR (400 MHz, CDCl₃): δ 12.15 (br, 1H), 9.47 (s, 1H), 7.85 (d, 1H), MS (ESI, pos. ion) 7.51 (d, 1H), 7.38-7.33 (m, 2H), 7.01 (td, 1H), 6.17 (s, 1H), 4.50 (d, 1H), m/z: 587.2 [M + H]⁺ 3.66 (d, 1H), 3.55 (s, 3H), 3.33-3.23 (m, 2H), 3.04-2.92 (m, 1H), 2.58-2.25 (m, 5H), 1.78-1.74 (m, 1H).

Example 8 The Preparation of (R)-ethyl 4-(2-chloro-4-fluorophenyl)-6-(morpholinomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate

Step 1) (R)—(S)-1-isopropoxy-1-oxopropan-2-yl 4-(2-chloro-4-fluorophenyl)-6-methyl-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate

Method One:

To a flask were added 2-thiazolecarboxamidine hydrochloride (16.4 g, 0.1 mol), 2-chloro-4-fluorobenzaldehyde (15.8 g, 0.1 mol), (S)-1-isopropoxy-1-oxopropan-2-yl 3-oxobutanoate (21.6 g, 0.1 mol), anhydrous sodium acetate (8.2 g, 0.1 mol) and i-propanol (74 g) in turn. The mixture was stirred at 80° C. for 16 hours. After the reaction, the mixture was cooled to 30° C., kept at 30° C. and stirred for 6 hours. The resulting mixture was filtered. The filter cake was washed with water (330 mL) and dried in vacuo at 60° C. for 8 hours to obtain the crude product. To the crude product was added i-propanol (74 g). The mixture was heated until dissolved completely, cooled to 30° C., and then kept at 30° C., stirred and crystallized for 3 hours. The resulting mixture was filtered. The filter cake was dried in vacuo at 60° C. for 8 hours to obtain the product as a yellow solid (6.05 g, 13%).

[a]_(D) ²⁵=−14.67 (c=0.2999 g/100 mL, MeOH);

MS (ESI, pos.ion) m/z: 466.0 [M+H]⁺;

¹H NMR (600 MHz, DMSO-d₆): δ 10.05 (s, 1H), 7.99 (d, 1H), 7.91 (d, 1H), 7.42-7.37 (m, 2H), 7.20 (td, 1H), 6.02 (s, 1H), 4.90-4.86 (m, 1H), 4.78 (q, 1H), 2.47 (s, 3H), 1.21 (d, 3H), 1.17 (d, 3H), 1.10 (d, 3H).

The compound 8 can be prepared under the reaction conditions shown in table 13 using method one described in step 1 of Example 8

TABLE 13 The reaction conditions

No. 1 2 3 4 5 (1)/(7)/(3)/(4) (mol) 1/1/2/1 1/1/1/1 1/1/1/1 1/1/1/1 1/1/1/1 (the amount of compound (1) is 16.4 g) Reaction solvent — i-propanol i-propanol i-propanol ethanol The mass ratio of reaction solvent — 1 3 20 4.5 to compound (1) Reaction temperature (° C.) 78 78 78 78 25 Reaction time (h) 12 12 6 12 77 Cooling temperature (° C.) 25 25 25 −40 25 Cooling time(h) 6 6 — 6 — Recrystallization solvent i-propanol i-propanol i-propanol i-propanol ethanol The mass ratio of recrystallization 8 6 4 3 10 solvent to compound (1) Crystallization temperature (° C.) 25 25 30 25 −30 Crystallization time (h) 6 10 6 4 8 Quality; 4.3 g; 9.2 4.9 g; 10.5 6.2 g; 13.2 4.7 g; 10.1 6.5 g; 14 yield(%) of product No. 6 7 8 9 10 (1)/(7)/(3)/(4)(mol) 1/1/1/1 1/1/1/1 1/1/1/1 1/1/1/1 1/1/1/1 (the amount of compound (1) is 16.4 g) Reaction solvent n-propanol 2-methoxy n-butanol t-butanol ethanol and ethanol water (v/v = 50:50) The mass ratio of reaction solvent to 3 3 2.5 3 3 compound (1) Reaction temperature (° C.) 78 78 78 78 78 Reaction time (h) 12 12 12 12 12 Cooling temperature (° C.) −10 −10 −15 30 30 Cooling time(h) 12 4 4 4 3 Recrystallization solvent n-propanol i-propanol i-propanol i-propanol i-propanol The mass ratio of recrystallization 3 3 3 3 3 solvent to compound (1) Crystallization temperature (° C.) −10 −20 −20 0 25 Crystallization time(h) 8 6 6 6 6 Quality; 3.9 g; 8.3 3.3 g; 7.1 4.6 g; 9.8 6.6 g; 14.2 6.3 g; 13.5 yield(%) of product

Method Two:

To a flask were added 2-thiazolecarboxamidine hydrochloride (16.4 g, 0.1 mol), 2-chloro-4-fluorobenzaldehyde (15.8 g, 0.1 mol), (S)-1-isopropoxy-1-oxopropan-2-yl 3-oxobutanoate (21.6 g, 0.1 mol), anhydrous sodium acetate (8.2 g, 0.1 mol) and i-propanol (74 g) in turn. The mixture was stirred at 80° C. for 16 hours. After the reaction, the mixture was cooled to 30° C., kept at 30° C. and stirred for 6 hours. The resulting mixture was filtered. The filter cake was washed with i-propanol (60 mL) followed by water (330 mL), and then dried in vacuo at 60° C. for 8 hours to obtain the product as a yellow solid (7.45 g, 16%).

[a]_(D) ²⁵=−14.67 (c=0.2999 g/100 mL, MeOH);

MS (ESI, pos.ion) m/z: 466.0 [M+H]⁺;

¹H NMR (600 MHz, DMSO-d₆): δ 10.05 (s, 1H), 7.99 (d, 1H), 7.91 (d, 1H), 7.42-7.37 (m, 2H), 7.20 (td, 1H), 6.02 (s, 1H), 4.90-4.86 (m, 1H), 4.78 (q, 1H), 2.47 (s, 3H), 1.21 (d, 3H), 1.17 (d, 3H), 1.10 (d, 3H).

The compound 8 can be prepared under the reaction conditions shown in table 14 using method two described in step 1 of Example 8

TABLE 14 The reaction conditions

No. 1 2 3 4 5 (1)/(7)/(3)/(4)(mol) 1/1/2/1 1/1/1/1 1/1/1/1 1/1/1/1 1/1/1/1 (the amount of compound (1) is 16.4 g) Reaction solvent — i-propanol i-propanol i-propanol ethanol The mass ratio of reaction solvent to — 1 4.5 20 4.5 compound (1) Reaction temperature(° C.) 78 78 78 78 25 Reaction time(h) 12 12 6 12 77 Cooling temperature(° C.) 30 25 25 −40 25 Cooling time(h) 6 6 4 6 — Washing solvent ethanol i-propanol i-propanol i-propanol ethanol The mass ratio of washing solvent to 10 6 — 1 3 compound (1) Washing temperature 25 25 25 25 25 Quality; 4.6 g; 9.8 5.5 g; 11.8 7.5 g; 16.2 5.5 g; 11.8 7.1 g; 15.3 yield(%) of product No. 6 7 8 9 10 (1)/(7)/(3)/(4)(mol) 1/1/1/1 1/1/1/1 1/1/1/1 1/1/1/1 1/1/1/1 (the amount of compound (1) is 16.4 g) Reaction solvent n-propanol 2-methoxy n-butanol t-butanol ethanol and ethanol water (v/v = 50:50) The mass ratio of reaction solvent to 3 3 2.5 3 3 compound (1) Reaction temperature(° C.) 78 78 78 78 78 Reaction time(h) 12 1 12 12 12 Cooling temperature(° C.) −10 −10 −15 30 30 Cooling time(h) 12 24 6 6 3 Washing solvent n-propanol i-propanol i-propanol i-propanol ethanol The mass ratio of washing solvent to 1 2 2 1 1 compound (1) Washing temperature 25 25 25 25 25 Quality; 4.4 g; 9.5 4.1 g; 8.9 5.3g; 11.3 7.2 g; 15.4 6.7 g; 14.4 yield(%) of product

Method Three:

To a flask were added 2-thiazolecarboxamidine hydrochloride (16.4 g, 0.1 mol), 2-chloro-4-fluorobenzaldehyde (15.8 g, 0.1 mol), (S)-1-isopropoxy-1-oxopropan-2-yl 3-oxobutanoate (21.6 g, 0.1 mol), anhydrous sodium acetate (8.2 g, 0.1 mol) and i-propanol (75 g) in turn. The mixture was stirred at 80° C. for 16 hours. After the reaction, the mixture was cooled to 30° C., kept at 30° C. and stirred for 6 hours. The resulting mixture was filtered. The filter cake was washed with water (330 mL), and then dried in vacuo at 60° C. for 8 hours to obtain the crude product. The crude product was triturated with i-propanol (60 mL) at 30° C. for 6 hours and filtered. The filter cake was dried in vacuo at 60° C. for 8 hours to obtain the product as a yellow solid (6.94 g, 14.9%).

[a]_(D) ²⁵=−14.67 (c=0.2999 g/100 mL, MeOH);

MS (ESI, pos.ion) m/z: 466.0 [M+H]⁺;

¹H NMR (600 MHz, DMSO-d₆): δ 10.05 (s, 1H), 7.99 (d, 1H), 7.91 (d, 1H), 7.42-7.37 (m, 2H), 7.20 (td, 1H), 6.02 (s, 1H), 4.90-4.86 (m, 1H), 4.78 (q, 1H), 2.47 (s, 3H), 1.21 (d, 3H), 1.17 (d, 3H), 1.10 (d, 3H).

The compound 8 can be prepared under the reaction conditions shown in table 15 using method three described in step 1 of Example 8

TABLE 15 The reaction conditions

No. 1 2 3 4 5 (1)/(7)/(3)/(4)(mol) 1/1/2/1 1/1/1/1 1/1/1/1 1/1/1/1 1/1/1/1 (the amount of compound (1) is 16.4 g) Reaction solvent — i-propanol i-propanol i-propanol ethanol The mass ratio of reaction solvent to — 1 4.5 20 4.5 compound (1) Reaction temperature(° C.) 78 78 78 78 25 Reaction time(h) 12 12 6 12 77 Cooling temperature(° C.) 30 25 25 −40 25 Cooling time(h) 6 6 4 6 − Trituration solvent ethanol i-propanol i-propanol i-propanol i-propanol The mass ratio of trituration solvent to 8 6 4 3 10 compound (1) Trituration temperature(° C.) 25 25 25 25 25 Trituration time(h) 2 5 6 3 2 Quality; 4.5 g; 9.6 5.2 g; 11.1 7.1 g; 15.3 5.3 g; 11.3 6.9 g; 14.8 yield (%) of product No. 6 7 8 9 10 (1)/(7)/(3)/(4)(mol) 1/1/1/1 1/1/1/1 1/1/1/1 1/1/1/1 1/1/1/1 (the amount of compound (1) is 16.4 g) Reaction solvent n-propanol 2-methoxy n-butanol t-butanol ethanol and ethanol water (v/v = 50:50) The mass ratio of reaction solvent to 3 3 2.5 3 3 compound (1) Reaction temperature(° C.) 78 78 78 78 78 Reaction time(h) 12 1 12 12 12 Cooling temperature(° C.) −10 −10 −15 30 30 Cooling time(h) 12 24 6 6 3 Trituration solvent n-propanol i-propanol i-propanol i-propanol ethanol The mass ratio of trituration solvent to 3 3 3 3 3 compound (1) Trituration temperature (° C.) 25 25 25 25 25 Trituration time(h) 5 6 4 6 4 Quality; 4.1 g; 8.9 3.8 g; 8.2 4.9 g; 10.5 6.9 g; 14.9 6.6 g; 14.1 yield (%) of product

Step 2) (R)—(S)-1-isopropoxy-1-oxopropan-2-yl 6-(bromomethyl)-4-(2-chloro-4-fluorophenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate

To a flask were added (R)—(S)-1-isopropoxy-1-oxopropan-2-yl 4-(2-chloro-4-fluorophenyl)-6-methyl-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (46.6 g, 0.1 mol) and dichloromethane (932 g) in turn. The mixture was heated at 35±5° C. until dissolved completely, and then to the mixture was added NBS (19.6 g, 0.11 mol), kept at this temperature and stirred for 30 min. After the reaction, the reaction mixture was concentrated. To the residue was added ethanol (186 g). The resulting mixture was cooled to 0° C., kept at this temperature and stirred. After solid precipitated out completely, the mixture was filtered. The filter cake was washed with ethanol (20 g) and dried in vacuo at 60° C. for 6 hours to obtain the product as a yellow solid (32.7 g, 60%).

MS (ESI, pos.ion) m/z: 544.1 [M+H]⁺;

¹H NMR (400 MHz, DMSO-d₆): δ 8.02 (d, 1H), 7.97 (d, 1H), 7.46-7.41 (m, 2H), 7.23 (td, 1H), 6.01 (s, 1H), 4.93-4.85 (m, 2H), 4.82-4.74 (m, 2H), 1.35 (d, 3H), 1.01 (d, 6H).

The compound A2 can be prepared under the reaction conditions shown in table 16 according to the procedure described in step 2 of Example 8

TABLE 16 Reaction conditions

No. 1 2 3 4 Compound (8)/NBS(mol) 1/1.1 1/1.05 1/1.15 1/1.1 the amount of compound (8) is 46.6 g Reaction solvent DCM DCM CHCl₃ CCl4 The mass ratio of reaction 30 15 20 20 solvent to compound (8) Reaction temperature(° C.) 39 39 61 76 The solvent added to i-propanol ethanol n-propanol ethanol the residue The mass ratio of the 7 5 5 4 addition of the solvent to compound (8) Quality; 34.3 g; 63 31.6 g; 58 33.8 g; 62 37.6 g; 69 yield(%) of product

Step 3) (R)—(S)-1-isopropoxy-1-oxopropan-2-yl 4-(2-chloro-4-fluorophenyl)-6-(morpholinomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate

To a flask were added (R)—(S)-1-isopropoxy-1-oxopropan-2-yl 4-(2-chloro-4-fluorophenyl)-6-(bromomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (54.5 g, 0.1 mol), i-propanol (327 g) and morpholine (34.8 g, 0.4 mol). The mixture was stirred at 55° C. for 4 hours. After the reaction, the mixture was cooled to 0° C., kept at 0° C. and stirred. After the solid precipitated out completely, the mixture was filtered. The filter cake was washed with i-propanol (54 g) followed by water (540 g), and then dried in vacuo at 60° C. for 8 hours to obtain the product as a yellowish solid (33 g, 60%).

MS (ESI, pos.ion) m/z: 551.2 [M+H];

¹H NMR (400 MHz, DMSO-d₆): δ 9.76 (s, 1H), 8.04 (d, 1H), 7.95 (d, 1H), 7.46-7.39 (m, 2H), 7.19 (td, 1H), 6.08 (s, 1H), 4.88-4.76 (m, 2H), 3.94 (dd, 2H), 3.68 (br, 4H), 2.59-2.53 (m, 4H), 1.33 (d, 3H), 1.03 (dd, 6H).

Step 4) (R)-ethyl 4-(2-chloro-4-fluorophenyl)-6-(morpholinomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate

To a flask were added anhydrous ethanol (440 g) and lithium (1.74 g, 0.25 mol) in turn. The mixture was stirred at 43° C. until the lithium was consumed entirely, and then a solution of (R)—(S)-1-isopropoxy-1-oxopropan-2-yl 4-(2-chloro-4-fluorophenyl)-6-(morpholinomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (55.1 g, 0.1 mol) in ethanol (440 g) was added. The reaction mixture was allowed to warm up to 78° C. and stirred for 1.5 hours. After the reaction, the reaction mixture was cooled and concentrated. To the residue was added ethyl acetate (551 g). The mixture was washed with water (200 g×2). The combined organic layers were concentrated to obtain the product as yellow thick oil (33.9 g, 73%).

MS (ESI, pos.ion) m/z: 465.2 [M+H]⁺;

¹H NMR (400 MHz, DMSO-d₆): δ 9.65 (s, 1H), 8.00 (d, 1H), 7.91 (d, 1H), 7.40-7.37 (m, 2H), 7.15 (td, 1H), 6.03 (s, 1H), 3.94 (q, 2H), 3.88 (dd, 2H), 3.65 (br, 4H), 2.56 (br, 4H), 1.05 (t, 3H).

Example 9 The Preparation of (R)-methyl 4-(2-chloro-4-fluorophenyl)-6-(morpholinomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate

To a flask were added anhydrous methanol (892 g) and lithium (1.74 g, 0.25 mol) in turn. The mixture was stirred at 43° C. until the lithium was consumed entirely, and then (R)—(S)-1-isopropoxy-1-oxopropan-2-yl 4-(2-chloro-4-fluorophenyl)-6-(morpholinomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (55.1 g, 0.1 mol) was added. The reaction mixture was allowed to warm up to 60° C. and stirred for 1.5 hours. After the reaction, the reaction mixture was cooled and concentrated. To the residue was added ethyl acetate (551 g). The mixture was washed with water (200 g×2). The combined organic layers were concentrated to obtain the product as yellow thick oil (31.6 g, 70%).

MS (ESI, pos.ion) m/z: 450.8 [M+H]⁺;

¹H NMR (600 MHz, DMSO-d₆): δ 9.72 (s, 1H), 8.03 (d, 1H), 7.94 (d, 1H), 7.43-7.38 (m, 2H), 7.17 (td, 1H), 6.05 (s, 1H), 3.93 (dd, 2H), 3.68 (br, 4H), 3.53 (s, 3H), 2.56 (br, 4H).

Example 10 The Preparation of (S)-4-(((R)-6-(2-chloro-4-fluorophenyl)-5-(ethoxycarbonyl)-2-(thiazol-2-yl)-3,6-dihydropyrimidin-4-yl)methyl)morpholine-3-carboxylicacid

Step 1) (S)-4-(((R)-6-(2-chloro-4-fluorophenyl)-5-((((S)-1-isopropoxy-1-oxopropan-2-yl)oxy)carbonyl)-2-(thiazol-2-yl)-3,6-dihydropyrimidin-4-yl)methyl)morpholine-3-carboxylic acid

To a flask were added (R)—(S)-1-isopropoxy-1-oxopropan-2-yl 4-(2-chloro-4-fluorophenyl)-6-(bromomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (54.5 g, 0.1 mol), ethanol (654 g), (S)-morpholine-3-carboxylic acid (13.1 g, 0.1 mol) and potassium carbonate (27.6 g, 0.2 mol) in turn. The mixture was stirred at 30° C. for 12 hours. After the reaction, the mixture was filtered. The filtrate was concentrated. To the residue was added water (900 g), the resulting mixture was extracted with ethyl acetate (900 mL), the organic layer was abandoned. To the aqueous layer was added ethyl acetate (900 mL), the mixture was adjusted to pH 3-6 with concentrated hydrochloric acid. The organic layer was dried over anhydrous sodium sulfate and concentrated to give the product as a yellow solid (47 g, 79%).

MS (ESI, pos.ion) m/z: 594.7 [M+H]⁺;

¹H NMR (400 MHz, DMSO-d₆): δ 9.93 (s, 1H), 8.03 (d, 1H), 7.93 (d, 1H), 7.45 (dd, 1H), 7.41 (dd, 1H), 7.17 (td, 1H), 6.07 (s, 1H), 4.86 (q, 1H), 4.81-4.76 (m, 1H), 4.31 (d, 1H), 4.06-4.02 (m, 2H), 3.83 (dd, 1H), 3.75-3.70 (m, 1H), 3.68-3.62 (m, 2H), 3.10-3.06 (m, 1H), 2.41-2.38 (m, 1H), 1.34 (d, 3H), 1.03 (t, 6H).

The compound Q can be prepared under the reaction conditions shown in table 17 according to the procedure described in step 1 of Example 10.

TABLE 17 The reaction conditions for preparation of compound Q

                No.

      Compound A2/ compound (VI) (mol) the amount of compound A2 is 5.45 g               Reaction solvent             Reaction temperature (° C.)               Reaction time(h)               Product character             Quality; yield(%) of product Q1

1/1 ethanol 30 12 yellow solid 3.99 g; 64 Q2

1/1 ethanol 30 12 yellow solid 3.68 g; 59 Q3

1/1 ethanol 30 12 yellow solid 3.05 g; 49 Q4

1/1 ethanol 30 12 yellow solid 4.32 g; 71 Q5

1/1 ethanol 30 12 yellow solid 3.7 g; 58 Q6

1/1 ethanol 30 12 yellow solid 4.5 g; 73 Q7

1/1 ethanol 30 12 yellow solid 4.1 g; 64 Q8

1/1 ethanol 30 12 yellow solid 3.92 g; 61

TABLE 17-1 The NMR and MS datum of compound Q No. ¹H NMR MS Q1 ¹H NMR (400 MHz, DMSO-d₆): δ 9.73 (s, 1H), 8.02 (d, 1H), 7.93 (d, 1H), MS (ESI, pos. ion) 7.44-7.38 (m, 2H), 7.18 (td, 1H), 6.07 (s, 1H), 4.85 (q, 1H), 4.81-4.75 (m, 1H), m/z: 622.7 [M + H]⁺ 3.89-3.86 (m, 3H), 3.60-3.51 (m, 2H), 2.77 (dd, 2H), 2.36-2.22 (m, 3H), 2.05-1.98 (m, 1H), 1.62 (dd, 2H), 1.32 (d, 3H), 1.03 (dd, 6H). Q2 ¹H NMR (600 MHz, DMSO-d₆): δ 12.11 (s, 1H), 9.75 (s, 1H), 8.01 (d, 1H), MS (ESI, pos. ion) 7.94 (d, 1H), 7.44-7.39 (m, 2H), 7.20 (td, 1H), 6.07 (s, 1H), 4.88 (q, 1H), m/z: 622.7 [M + H]⁺ 4.82-4.75 (m, 1H), 3.91-3.86 (m, 3H), 3.61-3.50 (m, 2H), 2.78 (dd, 2H), 2.37-2.22 (m, 3H), 2.04-1.97 (m, 1H), 1.63-1.59 (m, 2H), 1.32 (d, 3H), 1.03 (dd, 6H). Q3 ¹H NMR (400 MHz, DMSO-d₆): δ 12.11 (s, 1H), 9.72 (s, 1H), 8.02 (d, 1H), MS (ESI, pos. ion) 7.94 (d, 1H), 7.44-7.40 (m, 2H), 7.18 (td, 1H), 6.06 (s, 1H), 4.89 (q, 1H), m/z: 622.7 [M + H]⁺ 4.83-4.76 (m, 1H), 4.18 (d, 1H), 4.92-3.74 (m, 3H), 3.66-3.56 (m, 1H), 3.42-3.38 (m, 1H), 2.84-2.76 (m, 1H), 2.57-2.54 (m, 2H), 2.39-2.26 (m, 2H), 1.86-1.81 (m, 1H), 1.69-1.58 (m, 1H), 1.35 (d, 3H), 1.03 (dd, 6H). Q4 ¹H NMR (400 MHz, DMSO-d₆): δ 12.95 (s, 1H), 9.89 (s, 1H), 8.03 (d, 1H), MS (ESI, pos. ion) 7.94 (d, 1H), 7.46-7.38 (m, 2H), 7.19 (td, 1H), 6.05 (s, 1H), 4.87-4.75 (m, 2H), m/z: 609.2 [M + H]⁺ 4.10-4.02 (m, 1H), 3.91-3.87 (m, 1H), 3.75-3.62 (m, 3H), 3.42-3.39 (m, 1H), 3.01 (d, 1H), 2.91 (d, 1H), 1.32 (d, 3H), 1.21 (d, 3H), 1.03 (d, 6H). Q5 ¹H NMR (400 MHz, DMSO-d₆): δ 12.10 (s, 1H), 9.78 (s, 1H), 8.04 (d, 1H), MS (ESI, pos. ion) 7.96 (d, 1H), 7.43-7.38 (m, 2H), 7.18 (td, 1H), 6.05 (s, 1H), 4.86-4.77 (m, 2H), m/z: 637.2 [M + H]⁺ 4.16 (d, 1H), 3.86 (d, 1H), 3.77-3.75 (m, 1H), 3.59-3.55 (m, 1H), 3.52-3.46 (m, 1H), 2.69 (d, 1H), 2.46-2.41 (m, 1H), 2.37-2.31 (m, 3H), 2.06-1.89 (m, 1H), 1.79-1.72 (m, 1H), 1.30 (d, 3H), 1.22 (d, 3H), 1.05 (d, 6H). Q6 ¹H NMR (600 MHz, DMSO-d₆): δ 13.04 (br, 1H), 9.76 (s, 1H), 7.99 (d, 1H), MS (ESI, pos. ion) 7.92 (d, 1H), 7.46 (dd, 1H), 7.41 (dd, 1H), 7.20 (td, 1H), 6.05 (s, 1H), m/z: 615.2 [M + H]⁺ 4.87-4.77 (m, 2H), 4.33 (d, 1H), 4.09 (d, 1H), 3.95-3.90 (m, 1H), 3.54-3.48 (m, 1H), 3.40-3.15 (m, 1H), 3.14 (dd, 1H), 2.83-2.72 (m, 1H), 1.33 (d, 3H), 1.03 (d, 6H). Q7 ¹H NMR (600 MHz, DMSO-d₆): δ 12.05 (s, 1H), 9.58 (s, 1H), 8.01 (d, 1H), MS (ESI, pos. ion) 7.94 (d, 1H), 7.46 (dd, 1H), 7.41 (dd, 1H), 7.20 (td, 1H), 6.07 (s, 1H), m/z: 642.7 [M + H]⁺ 4.85 (q, 1H), 4.82-4.76 (m, 1H), 4.15 (d, 1H), 4.09 (d, 1H), 3.59-3.54 (m, 1H), 3.04-2.96 (m, 2H), 2.60-2.56 (m, 1H), 2.32-2.20 (m, 2H), 2.12-2.02 (m, 1H), 1.93-1.87 (m, 1H), 1.58-1.53 (m, 1H), 1.33 (d, 3H), 1.03 (d, 6H). Q8 ¹H NMR (600 MHz, DMSO-d₆): δ 12.15 (s, 1H), 9.52 (s, 1H), 8.01 (d, 1H), MS (ESI, pos. ion) 7.95 (d, 1H), 7.47 (dd, 1H), 7.41 (dd, 1H), 7.19 (td, 1H), 6.08 (s, 1H), m/z: 642.7 [M + H]⁺ 4.84 (q, 1H), 4.82-4.77 (m, 1H), 4.13 (dd, 2H), 3.48-3.38 (m, 1H), 3.03-2.97 (m, 1H), 2.94-2.85 (m, 1H), 2.62-2.58 (m, 1H), 2.38-2.33 (m, 1H), 2.31-2.25 (m, 1H), 2.14-2.07 (m, 1H), 2.06-2.01 (m, 1H), 1.66-1.58 (m, 1H), 1.34 (d, 3H), 1.03 (dd, 6H).

Step 2) (S)-4-(((R)-6-(2-chloro-4-fluorophenyl)-5-(ethoxycarbonyl)-2-(thiazol-2-yl)-3,6-dihydropyrimidin-4-yl)methyl)morpholine-3-carboxylic acid

To a flask were added anhydrous ethanol (446 g) and lithium (2.08 g, 0.3 mol) in turn. The mixture was stirred at 43° C. until the lithium was consumed entirely, and then a solution of (S)-4-(((R)-6-(2-chloro-4-fluorophenyl)-5-((((S)-1-isopropoxy-1-oxopropan-2-yl)oxy)carbonyl)-2-(thiazol-2-yl)-3,6-dihydropyrimidin-4-yl)methyl)morpholine-3-carboxylic acid (59.5 g, 0.1 mol) in ethanol (446 g) was added. The reaction mixture was allowed to warm up to 78° C. and stirred for 6 hours. After the reaction, the reaction mixture was cooled and concentrated. To the residue was added water (1200 g), the mixture was extracted with ethyl acetate (1000 mL). The mixture was partitioned. The organic layer was abandoned. To the aqueous layer was added ethyl acetate (1200 mL), the mixture was adjusted to pH 3-6 with concentrated hydrochloric acid. The organic layer was dried over anhydrous sodium sulfate and concentrated to give the product as a yellow solid (35.1 g, 69%).

MS (ESI, pos.ion) m/z: 509.2[M+H];

¹H NMR (400 MHz, DMSO-d₆): δ 13.00 (br, 1H), 9.95 (s, 1H), 8.02 (d, 1H), 7.93 (d, 1H), 7.46-7.38 (m, 2H), 7.17 (td, 1H), 6.05 (s, 1H), 4.20 (d, 1H), 4.05-4.02 (m, 1H), 3.97-3.91 (m, 3H), 3.81 (dd, 1H), 3.72-3.63 (m, 2H), 3.58-3.53 (m, 1H), 3.08-3.05 (m, 1H), 2.42-2.38 (m, 1H), 1.06 (t, 3H).

The compound X can be prepared under the reaction conditions shown in table 18 according to the procedure described in step 2 of Example 10.

TABLE 18 The reaction conditions for preparation of compound X

            No.             R³

    The mole ratio of Lithium to compound Q; the amount of compound Q           Reaction solvent         Reaction temperature (° C.)           Reaction time(h)           Product character         Quality yield(%) of product X1 ethyl

2.5; 6.23 g   ethanol 78 3 yellow solid 2.95 g; 55 X2 ethyl

3; 6.23 g ethanol 78 2 yellow solid 2.74 g; 51 X3 ethyl

5; 6.23 g ethanol 78 2 yellow solid 2.47 g; 46 X4 ethyl

6; 6.09 g ethanol 78 18 yellow solid 3.77 g; 72 X5 ethyl

3; 6.37 g ethanol 78 2 yellow solid 2.64 g; 48 X6 ethyl

3; 6.15 g ethanol 78 12 yellow solid 2.49 g; 47 X7 ethyl

5; 6.43 g ethanol 78 2 yellow solid 2.45 g; 44 X8 ethyl

4; 6.43 g ethanol 78 2 yellow solid 2.56 g; 46 X9 methyl

6; 5.95 g methanol 65 24 yellow solid 3.41 g; 69 X10 methyl

4; 6.23 g methanol 65 2 yellow solid 3.09 g; 59 X11 methyl

5; 6.23 g methanol 65 3 yellow solid 2.82 g; 54 X12 methyl

4; 6.23 g methanol 65 2 yellow solid 2.51 g; 48 X13 methyl

6; 6.09 g methanol 65 12 yellow solid 3.61 g; 71 X14 methyl

5; 6.37 g methanol 65 2 yellow solid 2.79 g; 52 X15 methyl

4; 6.15 g methanol 65 8 yellow solid 2.63 g; 51 X16 methyl

4; 6.43 g methanol 65 2 yellow solid 2.55 g; 47 X17 methyl

3; 6.43 g methanol 65 2 yellow solid 2.66 g; 49

TABLE 18-1 The NMR and MS datum of compound X No. ¹H NMR MS X1 ¹H NMR (400 MHz, DMSO-d₆): δ 9.65 (s, 1H), 8.02 (d, 1H), 7.94 (d, 1H), MS (ESI, pos. ion) m/z: 7.44-7.38 (m, 2H), 7.18 (td, 1H), 6.05 (s, 1H), 3.96 (q, 2H), 537.3 [M + H]⁺ 3.89-3.85 (m, 3H), 3.59-3.46 (m, 2H), 2.80-2.74 (m, 2H), 2.36-2.21 (m, 3H), 2.03-1.98 (m, 1H), 1.64-1.59 (m, 2H), 1.06 (t, 3H). X2 ¹H NMR (400 MHz, DMSO-d₆): δ 12.07 (s, 1H), 9.65 (s, 1H), 8.02 (d, 1H), MS (ESI, pos. ion) m/z: 7.94 (d, 1H), 7.44-7.40 (m, 2H), 7.19 (td, 1H), 6.06 (s, 1H), 3.97 (q, 2H), 536.9 [M + H]⁺ 3.92-3.82 (m, 3H), 3.58-3.46 (m, 2H), 2.88 (d, 1H), 2.63 (d, 1H), 2.37-2.22 (m, 3H), 2.08-1.99 (m, 1H), 1.72-1.65 (m, 2H), 1.05 (t, 3H). X3 ¹H NMR (400 MHz, DMSO-d₆): δ 12.13 (br, 1H), 9.81 (s, 1H), MS (ESI, pos. ion) m/z: 8.02 (d, 1H), 7.94 (d, 1H), 7.44-7.38 (m, 2H), 7.18 (td, 1H), 6.02 (s, 1H), 537.2 [M + H]⁺ 4.20 (d, 1H), 3.98 (q, 2H), 3.92 (d, 1H), 3.83-3.78 (m, 1H), 3.75-3.72 (m, 1H), 3.62-3.58 (m, 1H), 3.37-3.33 (m, 1H), 2.79-2.75 (m, 1H), 2.58-2.53 (m, 1H), 2.49-2.46 (m, 1H), 2.39-2.32 (m, 2H), 1.89-1.83 (m, 1H), 1.66-1.58 (m, 1H), 1.06 (t, 3H). X4 ¹H NMR (600 MHz, DMSO-d₆): δ 13.00 (s, 1H), 9.78 (s, 1H), 8.03 (d, 1H), MS (ESI, pos. ion) m/z: 7.93 (d, 1H), 7.43-7.30 (m, 2H), 7.18 (td, 1H), 6.03 (s, 1H), 4.06 (d, 1H), 523.2 [M + H]⁺ 3.95 (q, 2H), 3.90 (d, 1H), 3.74-3.69 (m, 2H), 3.65-3.60 (m, 1H), 2.98 (d, 1H), 2.89 (d, 1H), 2.49-2.45 (m, 1H), 1.21 (d, 3H), 1.04 (t, 3H). X5 ¹H NMR (400 MHz, DMSO-d₆): δ 12.12 (s, 1H), 9.75 (s, 1H), 8.02 (d, 1H), MS (ESI, pos. ion) m/z: 7.95 (d, 1H), 7.42-7.36 (m, 2H), 7.15 (td, 1H), 6.06 (s, 1H), 4.15 (d, 1H), 551.2 [M + H]⁺ 4.02-3.91 (m, 2H), 3.86 (d, 1H), 3.75-3.73 (m, 1H), 3.59-3.54 (m, 1H), 3.51-3.45 (m, 1H), 2.66 (d, 1H), 2.46-2.40 (m, 1H), 2.37-2.30 (m, 3H), 2.03-1.92 (m, 1H), 1.80-1.74 (m, 1H), 1.20 (d, 3H), 1.06 (t, 3H). X6 ¹H NMR (600 MHz, DMSO-d₆): δ 13.01 (br, 1H), 9.66 (s, 1H), MS (ESI, pos. ion) m/z: 7.98 (d, 1H), 7.91 (d, 1H), 7.45-7.41 (m, 2H), 7.19 (td, 1H), 6.04 (s, 1H), 529.1 [M + H]⁺ 4.33 (d, 1H), 4.08 (d, 1H), 4.05-4.02 (m, 1H), 3.97 (q, 2H), 3.92-3.89 (m, 1H), 3.53-3.48 (m, 1H), 3.19-3.12 (m, 1H), 2.82-2.72 (m, 1H), 1.05 (t, 3H). X7 ¹H NMR (400 MHz, DMSO-d₆): δ 12.08 (s, 1H), 9.52 (s, 1H), 7.99 (d, 1H), MS (ESI, pos. ion) m/z: 7.92 (d, 1H), 7.44-7.40 (m, 2H), 7.19 (td, 1H), 6.03 (s, 1H), 4.13 (dd, 2H), 556.9 [M + H]⁺ 3.97 (q, 2H), 3.60-3.52 (m, 1H), 3.06-2.96 (m, 2H), 2.59-2.56 (m, 1H), 2.36-2.20 (m, 2H), 2.13-1.99 (m, 1H), 1.93-1.88 (m, 1H), 1.57-1.44 (m, 1H), 1.05 (t, 3H). X8 ¹H NMR (400 MHz, DMSO-d₆): δ 12.16 (br, 1H), 9.45 (s, 1H), MS (ESI, pos. ion) m/z: 8.00 (d, 1H), 7.94 (d, 1H), 7.47-7.41 (m, 2H), 7.18 (td, 1H), 6.06 (s, 1H), 557.2 [M + H]⁺ 4.12 (dd, 2H), 4.00-3.93 (m, 2H), 3.46-3.38 (m, 1H), 3.01-2.85 (m, 2H), 2.60-2.53 (m, 1H), 2.40-2.23 (m, 2H), 2.15-1.99 (m, 2H), 1.66-1.56 (m, 1H), 1.05 (t, 3H). X9 ¹H NMR (400 MHz, DMSO-d₆): δ 12.52 (br, 1H), 9.86 (s, 1H), MS (ESI, pos. ion) m/z: 8.03 (d, 1H), 7.94 (d, 1H), 7.43-7.38 (m, 2H), 7.16 (td, 1H), 6.04 (s, 1H), 494.9 [M + H]⁺ 4.24 (d, 1H), 4.06-3.97 (m, 2H), 3.84 (dd, 1H), 3.73-3.66 (m, 2H), 3.64-3.59 (m, 1H), 3.51 (s, 3H), 3.10-3.06 (m, 1H), 2.43-2.39 (m, 1H). X10 ¹H NMR (400 MHz, DMSO-d₆): δ 12.12 (s, 1H), 9.71 (s, 1H), 8.03 (d, 1H), MS (ESI, pos. ion) m/z: 7.96 (d, 1H), 7.44-7.38 (m, 2H), 7.18 (td, 1H), 6.02 (s, 1H), 522.9 [M + H]⁺ 3.94-3.82 (m, 3H), 3.62-3.54 (m, 2H), 3.53 (s, 3H), 2.78 (dd, 2H), 2.38-2.26 (m, 3H), 2.06-1.99 (m, 1H), 1.66-1.59 (m, 2H). X11 ¹H NMR (400 MHz, DMSO-d₆): δ 12.09 (br, 1H), 9.70 (s, 1H), MS (ESI, pos. ion) m/z: 8.03 (d, 1H), 7.94 (d, 1H), 7.44-7.38 (m, 2H), 7.18 (td, 1H), 6.04 (s, 1H), 523.2 [M + H]⁺ 3.95 (d, 1H), 3.86-3.81 (m, 2H), 3.57-3.54 (m, 1H), 3.52 (s, 3H), 3.50-3.47 (m, 1H), 2.87 (d, 1H), 2.62 (d, 1H), 2.35-2.19 (m, 3H), 2.14-2.08 (m, 1H), 1.73-1.61 (m, 2H). X12 ¹H NMR (400 MHz, DMSO-d₆): δ 9.87 (s, 1H), 8.03 (d, 1H), 7.94 (d, 1H), MS (ESI, pos. ion) m/z: 7.44-7.40 (m, 2H), 7.16 (td, 1H), 6.02 (s, 1H), 4.20 (d, 1H), 3.93 (d, 1H), 523.1 [M + H]⁺ 3.84-3.79 (m, 1H), 3.75-3.71 (m, 1H), 3.62-3.56 (m, 1H), 3.52 (s, 3H), 3.48-3.41 (m, 1H), 3.05-2.87 (m, 1H), 2.78-2.75 (m, 1H), 2.58-2.56 (m, 1H), 2.38-2.23 (m, 2H), 1.87-1.84 (m, 1H), 1.66-1.58 (m, 1H). X13 ¹H NMR (600 MHz, DMSO-d₆): δ 13.01 (s, 1H), 9.83 (s, 1H), 8.02 (d, 1H), MS (ESI, pos. ion) m/z: 7.93 (d, 1H), 7.42-7.38 (m, 2H), 7.17 (td, 1H), 6.02 (s, 1H), 4.07 (d, 1H), 508.7 [M + H]⁺ 3.89 (d, 1H), 3.76-3.62 (m, 3H), 3.51 (s, 3H), 3.47-3.43 (m, 1H), 2.98 (d, 1H), 2.89 (d, 1H), 1.20 (d, 3H). X14 ¹H NMR (400 MHz, DMSO-d₆): δ 12.11 (s, 1H), 9.76 (s, 1H), 8.02 (d, 1H), MS (ESI, pos. ion) m/z: 7.96 (d, 1H), 7.44-7.40 (m, 2H), 7.16 (td, 1H), 6.01 (s, 1H), 4.16 (d, 1H), 537.1 [M + H]⁺ 3.88 (d, 1H), 3.78-3.74 (m, 1H), 3.60-3.55 (m, 1H), 3.53 (s, 3H), 3.50-3.46 (m, 1H), 2.68 (d, 1H), 2.48-2.42 (m, 1H), 2.36-2.31 (m, 3H), 2.04-1.93 (m, 1H), 1.82-1.73 (m, 1H), 1.21 (d, 3H). X15 ¹H NMR (600 MHz, DMSO-d₆): δ 9.70 (br, 1H), 8.01 (d, 1H), 7.92 (d, 1H), MS (ESI, pos. ion) m/z: 7.44-7.38 (m, 2H), 7.18 (td, 1H), 6.01 (s, 1H), 4.31 (d, 1H), 4.09 (d, 1H), 515.1 [M + H]⁺ 3.94-3.89 (m, 1H), 3.53 (s, 3H), 3.48-3.44 (m, 1H), 3.23-3.07 (m, 2H), 2.84-2.75 (m, 1H). X16 ¹H NMR (400 MHz, DMSO-d₆): δ 12.07 (br, 1H), 9.55 (s, 1H), MS (ESI, pos. ion) m/z: 7.99 (d, 1H), 7.92 (d, 1H), 7.43-7.39 (m, 2H), 7.18 (td, 1H), 6.03 (s, 1H), 543.0 [M + H]⁺ 4.15 (d, 1H), 4.09 (d, 1H), 3.56-3.54 (m, 1H), 3.53 (s, 3H), 3.05-2.95 (m, 2H), 2.48-2.46 (m, 1H), 2.36-2.17 (m, 2H), 2.15-2.02 (m, 1H), 1.97-1.85 (m, 1H), 1.59-1.50 (m, 1H). X17 ¹H NMR (400 MHz, DMSO-d₆): δ 12.06 (br, 1H), 9.56 (s, 1H), MS (ESI, pos. ion) m/z: 8.01 (d, 1H), 7.94 (d, 1H), 7.44-7.40 (m, 2H), 7.16 (td, 1H), 6.05 (s, 1H), 543.0 [M + H]⁺ 4.13 (d, 1H), 4.09 (d, 1H), 3.57-3.54 (m, 1H), 3.52 (s, 3H), 3.06-2.96 (m, 2H), 2.47-2.45 (m, 1H), 2.37-2.17 (m, 2H), 2.16-2.02 (m, 1H), 1.98-1.85 (m, 1H), 1.60-1.51 (m, 1H).

Example 11 The Preparation of (R)-ethyl 4-(2-chloro-4-fluorophenyl)-6-(morpholinomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate

Step 1) (R)-ethyl 4-(2-chloro-4-fluorophenyl)-6-methyl-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate

To a flask were added anhydrous ethanol (350 g) and lithium (2.43 g, 0.35 mol) in turn. The mixture was stirred at 43° C. until the lithium was consumed entirely, and then a solution of (R)—(S)-1-isopropoxy-1-oxopropan-2-yl 4-(2-chloro-4-fluorophenyl)-6-methyl-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (46.6 g, 0.1 mol) in ethanol (350 g) was added. The reaction mixture was allowed to warm up to 78° C. and stirred for 6 hours under nitrogen atmosphere. After the reaction, the reaction mixture was cooled to 10° C., kept at 10° C. and stirred for 8 hours. The mixture was filtered. The filtrate was washed with anhydrous ethanol (50 g) and water (510 g) in turn, and then dried in vacuo at 60° C. for 8 hours to obtain the product as a yellow solid (20.9 g, 55%).

[a]_(D) ²⁵=−59.6 (c=0.3020 g/100 mL, MeOH);

MS (ESI, pos.ion) m/z: 380.2 [M+H]⁺;

¹H NMR (600 MHz, DMSO-d₆): δ 9.92 (s, 1H), 7.97 (d, 1H), 7.90 (d, 1H), 7.41 (dd, 1H), 7.37 (dd, 1H), 7.19 (td, 1H), 6.00 (s, 1H), 3.93 (q, 2H), 2.46 (s, 3H), 1.03 (t, 3H).

The compound T can be prepared under the reaction conditions shown in table 19 according to the procedure described in step 1 of Example 11.

TABLE 19 The reaction conditions for preparation of compound T

The mole ratio of Lithium to compound (8); The mass ratio the amount of of reaction Reaction Quality; compound (8)is Reaction solvent to temperature Reaction Product yield(%) No. R³ 46.6 g solvent compound (8) (° C.) time (h) character of product T1 ethyl 2.5 ethanol 10 78 12 yellow solid 17.5 g; 46 T1 ethyl 3 ethanol 6 78 8 yellow solid 26.9 g; 71 T1 ethyl 4 ethanol 10 78 4 yellow solid 26.6 g; 70 T1 ethyl 5 ethanol 20 78 24 yellow solid 26.2 g; 69 T1 ethyl 6 ethanol 30 78 12 yellow solid 23.2 g; 61 T1 ethyl 8 ethanol 20 78 12 yellow solid 25.8 g; 68 T2 methyl 2.5 methanol 4 64 20 yellow solid 17.9 g; 49 T2 methyl 3 methanol 6 64 6 yellow solid   19 g; 52 T2 methyl 4 methanol 8 64 8 yellow solid 17.6 g; 48 T2 methyl 3 methanol 10 64 10 yellow solid 17.2 g; 47 T2 methyl 3 methanol 20 64 3 yellow solid 14.3 g; 39

TABLE 19-1 The NMR, MS and specific rotation datum of the compound T No. ¹H NMR MS specific rotation T1 ¹H NMR (600 MHz, DMSO-d₆): δ 9.92 (s, 1H), MS (ESI, pos. ion) m/z: [a]_(D) ²⁵ = −59.6 (c = 0.3020 g/ 7.97 (d, 1H), 7.90 (d, 1H), 7.41 (dd, 1H), 7.37 (dd, 1H), 380.2 [M + H]⁺ 100 mL, 7.19 (td, 1H), 6.00 (s, 1H), 3.93 (q, 2H), 2.46 (s, 3H), MeOH) 1.03 (t, 3H). T2 ¹H NMR (400 MHz, DMSO-d₆): δ 7.81 (d, 1H), MS (ESI, pos. ion) m/z: [a]_(D) ²⁵ = −81.49 (c = 0.5031 g/ 7.68 (d, 1H), 7.36 (dd, 1H), 7.29 (dd, 1H), 7.11 (td, 1H), 366.1 [M + H]⁺ 100 mL, 5.90 (s, 1H), 3.41 (s, 3H), 2.34 (s, 3H). MeOH)

Step 2) (R)-ethyl 4-(2-chloro-4-fluorophenyl)-6-(bromomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate

To a flask were added (R)-ethyl 4-(2-chloro-4-fluorophenyl)-6-methyl-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (38 g, 0.1 mol) and CCl₄ (760 g), followed by NBS (19.6 g, 0.11 mol) at 70° C. The mixture was stirred for 30 min. After the reaction, the mixture was cooled and filtered. The filtrate was concentrated to obtain the product as a yellow solid (37.6 g, 82%).

MS (ESI, pos.ion) m/z: 457.9 [M+H];

¹H NMR (400 MHz, DMSO-d₆): δ 9.67 (s, 1H), 8.01 (d, 1H), 7.97 (br, 1H), 7.44-7.41 (m, 2H), 7.22 (td, 1H), 5.99 (s, 1H), 4.83 (br, 2H), 4.02 (q, 2H), 1.07 (t, 3H).

The compound W can be prepared under the reaction conditions shown in table 20 according to the procedure described in step 2 of Example 11.

TABLE 20 The reaction conditions for preparation of compound W

The mole ratio of NBS to compound (T); The mass ratio of Reaction Quality; the amount of Reaction reaction solvent to temperature Product yield(%) No. R³ compound (T) solvent compound (T); (° C.) character of product W1 ethyl   1.0; 38 g DCM 10 39 yellow solid 37.2 g; 81 W1 ethyl   1.0; 38 g CHCl₃ 20 61 yellow solid 35.8 g; 78 W1 ethyl   1.1; 38 g CCl₄ 30 76 yellow solid 38.6 g; 84 W2 methyl 1.0; 36.6 g DCM 10 39 yellow solid   32 g; 72 W2 methyl 1.1; 36.6 g CHCl₃ 20 61 yellow solid 32.5 g; 73 W2 methyl 1.1; 36.6 g CCl₄ 30 76 yellow solid 36.5 g; 82

TABLE 20-1 The NMR and MS datum of the compound W No. ¹H NMR MS W1 ¹H NMR (400 MHz, DMSO-d₆): δ 9.62 (s, 1H), 8.01 (d, 1H), 7.92 (d, 1H), MS (ESI, pos. ion) 7.44-7.38 (m, 2H), 7.18 (td, 1H), 6.04 (s, 1H), 4.94 (d, 1H), 4.62 (d, 1H), m/z: 457.9 [M + H]⁺ 4.15 (q, 2H), 1.12 (t, 3H). W2 ¹H NMR (600 MHz, DMSO-d₆): δ 8.02 (d, 1H), 7.96 (br, 1H), MS (ESI, pos. ion) 7.46-7.40 (m, 2H), 7.22 (td, 1H), 5.98 (s, 1H), 4.83 (br, 2H), 3.57 (s, 3H). m/z: 445.6 [M + H]⁺

Step 3) (R)-ethyl 4-(2-chloro-4-fluorophenyl)-6-(morpholinomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate

To a flask were added (R)-ethyl 4-(2-chloro-4-fluorophenyl)-6-(bromomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (45.9 g, 0.1 mol), anhydrous ethanol (275 g) and morpholine (34.8 g, 0.4 mol). The mixture was stirred at 25° C. under nitrogen atmosphere for 6 hours. After the reaction, the mixture was concentrated. To the residue was added ethyl acetate (500 g), the resulting mixture was washed with water (250 mL×2). The organic layer was concentrated to give the product as tawny oil (35.8 g, 77%)

MS (ESI, pos.ion) m/z: 465.2 [M+H]⁺;

¹H NMR (400 MHz, DMSO-d₆): δ 9.65 (s, 1H), 8.00 (d, 1H), 7.91 (d, 1H), 7.40-7.37 (m, 2H), 7.15 (td, 1H), 6.03 (s, 1H), 3.94 (q, 2H), 3.88 (dd, 2H), 3.65 (br, 4H), 2.56 (br, 4H), 1.05 (t, 3H).

The compound U can be prepared under the reaction conditions shown in table 21 according to the procedure described in step 3 of Example 11.

TABLE 21 The reaction conditions for preparation of compound U

The mole ratio of The mass ratio compound (6) to of reaction compound (W); solvent to Reaction Quality; the amount of Reaction compound temperature Reaction Product yield(%) No. R³ compound (W) solvent (W); (° C.) time(h) character of product U1 ethyl 2; 45.9 g ethanol 20 25 2 tawny oil   34 g; 73 U1 ethyl 3; 45.9 g acetone 10 40 10 tawny oil 36.3 g; 78 U1 ethyl 4; 45.9 g methanol 10 30 6 tawny oil 33.5 g; 72 U1 ethyl 5; 45.9 g ethyl acetate 20 50 24 tawny oil 34.4 g; 74 U1 ethyl 6; 45.9 g DCM 8 39 6 tawny oil   33 g; 71 U1 ethyl 3; 45.9 g DMF 4 60 1 tawny oil 31.6 g; 68 U1 ethyl 4; 45.9 g THF 6 50 8 tawny oil 33.5 g; 72 U2 methyl 2; 44.5 g ethanol 20 25 2 tawny oil 33.8 g; 75 U2 methyl 3; 44.5 g acetone 10 40 10 tawny oil 32.4 g; 72 U2 methyl 4; 44.5 g methanol 10 30 6 tawny oil 34.6 g; 77 U2 methyl 5; 44.5 g ethyl acetate 20 50 24 tawny oil 33.3 g; 74 U2 methyl 6; 44.5 g DCM 8 39 6 tawny oil 30.2 g; 67 U2 methyl 3; 44.5 g DMF 4 60 1 tawny oil   32 g; 71 U2 methyl 4; 44.5 g THF 6 50 8 tawny oil 30.6 g; 68

TABLE 21-1 The NMR and MS datum of the compound U No. ¹H NMR MS U1 ¹H NMR (400 MHz, DMSO-d₆): δ 9.65 (s, 1H), 8.00 (d, 1H), 7.91 (d, 1H), MS (ESI, pos. ion) 7.40-7.37 (m, 2H), 7.15 (td, 1H), 6.03 (s, 1H), 3.94 (q, 2H), 3.88 (dd, 2H), m/z: 465.2 [M + H]⁺ 3.65 (br, 4H), 2.56 (br, 4H), 1.05 (t, 3H). U2 ¹H NMR (600 MHz, DMSO-d₆): δ 9.72 (s, 1H), 8.03 (d, 1H), MS (ESI, pos. ion) 7.94 (d, 1H), 7.43-7.38 (m, 2H), 7.17 (td, 1H), 6.05 (s, 1H), 3.93 (dd, 2H), 3.68 (br, 4H), m/z: 450.8 [M + H]⁺ 3.53 (s, 3H), 2.56 (br, 4H).

Example 12 The Preparation of (S)-4-(((R)-6-(2-chloro-4-fluorophenyl)-5-(ethoxycarbonyl)-2-(thiazol-2-yl)-3,6-dihydropyrimidin-4-yl)methyl)morpholine-3-carboxylic acid

To a flask were added (R)-ethyl 4-(2-chloro-4-fluorophenyl)-6-(bromomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (4.59 g, 10 mmol), (S)-morpholine-3-carboxylic acid (1.31 g, 10 mmol), potassium carbonate (2.76 g, 20 mmol) and ethanol (90 mL). The mixture was stirred at 30° C. under nitrogen atmosphere for 12 hours. After the reaction, the mixture was filtered. The filtrate was concentrated. To the residue was added water (100 mL). The resulting mixture was extracted with ethyl acetate (100 mL). The organic phase was abandoned. To the aqueous layer was added ethyl acetate (100 mL), the mixture was adjusted to pH 3-6 with concentrated hydrochloric acid. After partitioned, the organic layer was dried over anhydrous sodium sulfate and concentrated to give the product as a yellow solid (3.96 g, 78%).

MS (ESI, pos.ion) m/z: 509.2[M+H];

¹H NMR (400 MHz, DMSO-d₆): δ 13.00 (br, 1H), 9.95 (s, 1H), 8.02 (d, 1H), 7.93 (d, 1H), 7.46-7.38 (m, 2H), 7.17 (td, 1H), 6.05 (s, 1H), 4.20 (d, 1H), 4.05-4.02 (m, 1H), 3.97-3.91 (m, 3H), 3.81 (dd, 1H), 3.72-3.63 (m, 2H), 3.58-3.53 (m, 1H), 3.08-3.05 (m, 1H), 2.42-2.38 (m, 1H), 1.06 (t, 3H).

The compound X can be prepared under the reaction conditions shown in table 22 according to the procedure described in Example 12.

TABLE 22 The reaction conditions for preparation of compound X

                  No.                   R³

      The mole ratio of compound (W) to compound (VI); the amount of compound (W)                 Reaction solvent         The mass ratio of reaction solvent to compound (W):               Reaction temperature (° C.)                 Reaction time(h)                 Product character             Quality; yield(%) of product X1 ethyl

1; 4.59 g ethanol 20 30 4 yellow solid 3.65 g; 68 X2 ethyl

1; 4.59 g ethanol 15 30 6 yellow solid   3.6 g; 67 X3 ethyl

1; 4.59 g ethanol 10 30 12 yellow solid 2.31 g; 43 X4 ethyl

1; 4.59 g ethanol 4 30 24 yellow solid   4.1 g; 78 X5 ethyl

1; 4.59 g ethanol 12 30 16 yellow solid 2.76 g; 50 X6 ethyl

1; 4.59 g ethanol 20 30 24 yellow solid 3.97 g; 75 X7 ethyl

1; 4.59 g ethanol 10 30 12 yellow solid 3.45 g; 62 X8 ethyl

1; 4.59 g ethanol 15 30 18 yellow solid   3.4 g; 61 X9 methyl

1; 4.45 g ethanol 6 30 24 yellow solid 3.47 g; 70 X10 methyl

1; 4.45 g ethanol 10 30 12 yellow solid 3.45 g; 66 X11 methyl

1; 4.45 g ethanol 20 30 16 yellow solid 3.29 g; 63 X12 methyl

1; 4.45 g ethanol 15 30 20 yellow solid 2.2 g; 42 X13 methyl

1; 4.45 g ethanol 30 30 2 yellow solid 3.82 g; 75 X14 methyl

1; 4.45 g ethanol 8 30 10 yellow solid 2.47 g; 46 X15 methyl

1; 4.45 g ethanol 15 30 16 yellow solid 3.71 g; 72 X16 methyl

1; 4.45 g ethanol 10 30 8 yellow solid   3.2 g; 59 X17 methyl

1; 4.45 g ethanol 20 30 8 yellow solid 3.15 g; 58

TABLE 22-1 The NMR and MS datum of the compound X No. ¹H NMR MS X1 ¹H NMR (400 MHz, DMSO-d₆): δ 9.65 (s, 1H), 8.02 (d, 1H), 7.94 (d, 1H), MS (ESI, pos. ion) 7.44-7.38 (m, 2H), 7.18 (td, 1H), 6.05 (s, 1H), 3.96 (q, 2H), 3.89-3.85 (m, 3H), m/z: 537.3 [M + H]⁺ 3.59-3.46 (m, 2H), 2.80-2.74 (m, 2H), 2.36-2.21 (m, 3H), 2.03-1.98 (m, 1H), 1.64-1.59 (m, 2H), 1.06 (t, 3H). X2 ¹H NMR (400 MHz, DMSO-d₆): δ 12.07 (s, 1H), 9.65 (s, 1H), 8.02 (d, 1H), MS (ESI, pos. ion) 7.94 (d, 1H), 7.44-7.40 (m, 2H), 7.19 (td, 1H), 6.06 (s, 1H), 3.97 (q, 2H), m/z: 536.9 [M + H]⁺ 3.92-3.82 (m, 3H), 3.58-3.46 (m, 2H), 2.88 (d, 1H), 2.63 (d, 1H), 2.37-2.22 (m, 3H), 2.08-1.99 (m, 1H), 1.72-1.65 (m, 2H), 1.05 (t, 3H). X3 ¹H NMR (400 MHz, DMSO-d₆): δ 12.13 (br, 1H), 9.81 (s, 1H), 8.02 (d, 1H), MS (ESI, pos. ion) 7.94 (d, 1H), 7.44-7.38 (m, 2H), 7.18 (td, 1H), 6.02 (s, 1H), 4.20 (d, 1H), 3.98 (q, 2H), m/z: 537.2 [M + H]⁺ 3.92 (d, 1H), 3.83-3.78 (m, 1H), 3.75-3.72 (m, 1H), 3.62-3.58 (m, 1H), 3.37-3.33 (m, 1H), 2.79-2.75 (m, 1H), 2.58-2.53 (m, 1H), 2.49-2.46 (m, 1H), 2.39-2.32 (m, 2H), 1.89-1.83 (m, 1H), 1.66-1.58 (m, 1H), 1.06 (t, 3H). X4 ¹H NMR (600 MHz, DMSO-d₆): δ 13.00 (s, 1H), 9.78 (s, 1H), 8.03 (d, 1H), MS (ESI, pos. ion) 7.93 (d, 1H), 7.43-7.30 (m, 2H), 7.18 (td, 1H), 6.03 (s, 1H), 4.06 (d, 1H), 3.95 (q, 2H), m/z: 523.2 [M + H]⁺ 3.90 (d, 1H), 3.74-3.69 (m, 2H), 3.65-3.60 (m, 1H), 2.98 (d, 1H), 2.89 (d, 1H), 2.49-2.45 (m, 1H), 1.21 (d, 3H), 1.04 (t, 3H). X5 ¹H NMR (400 MHz, DMSO-d₆): δ 12.12 (s, 1H), 9.75 (s, 1H), 8.02 (d, 1H), MS (ESI, pos. ion) 7.95 (d, 1H), 7.42-7.36 (m, 2H), 7.15 (td, 1H), 6.06 (s, 1H), 4.15 (d, 1H), m/z: 551.2 [M + H]⁺ 4.02-3.91 (m, 2H), 3.86 (d, 1H), 3.75-3.73 (m, 1H), 3.59-3.54 (m, 1H), 3.51-3.45 (m, 1H), 2.66 (d, 1H), 2.46-2.40 (m, 1H), 2.37-2.30 (m, 3H), 2.03-1.92 (m, 1H), 1.80-1.74 (m, 1H), 1.20 (d, 3H), 1.06 (t, 3H). X6 ¹H NMR (600 MHz, DMSO-d₆): δ 13.01 (br, 1H), 9.66 (s, 1H), 7.98 (d, 1H), MS (ESI, pos. ion) 7.91 (d, 1H), 7.45-7.41 (m, 2H), 7.19 (td, 1H), 6.04 (s, 1H), 4.33 (d, 1H), 4.08 (d, 1H), m/z: 529.1 [M + H]⁺ 4.05-4.02 (m, 1H), 3.97 (q, 2H), 3.92-3.89 (m, 1H), 3.53-3.48 (m, 1H), 3.19-3.12 (m, 1H), 2.82-2.72 (m, 1H), 1.05 (t, 3H). X7 ¹H NMR (400 MHz, DMSO-d₆): δ 12.08 (s, 1H), 9.52 (s, 1H), 7.99 (d, 1H), MS (ESI, pos. ion) 7.92 (d, 1H), 7.44-7.40 (m, 2H), 7.19 (td, 1H), 6.03 (s, 1H), 4.13 (dd, 2H), 3.97 (q, 2H), m/z: 556.9 [M + H]⁺ 3.60-3.52 (m, 1H), 3.06-2.96 (m, 2H), 2.59-2.56 (m, 1H), 2.36-2.20 (m, 2H), 2.13-1.99 (m, 1H), 1.93-1.88 (m, 1H), 1.57-1.44 (m, 1H), 1.05 (t, 3H). X8 ¹H NMR (400 MHz, DMSO-d₆): δ 12.16 (br, 1H), 9.45 (s, 1H), 8.00 (d, 1H), MS (ESI, pos. ion) 7.94 (d, 1H), 7.47-7.41 (m, 2H), 7.18 (td, 1H), 6.06 (s, 1H), 4.12 (dd, 2H), m/z: 557.2 [M + H]⁺ 4.00-3.93 (m, 2H), 3.46-3.38 (m, 1H), 3.01-2.85 (m, 2H), 2.60-2.53 (m, 1H), 2.40-2.23 (m, 2H), 2.15-1.99 (m, 2H), 1.66-1.56 (m, 1H), 1.05 (t, 3H). X9 ¹H NMR (400 MHz, DMSO-d₆): δ 12.52 (br, 1H), 9.86 (s, 1H), 8.03 (d, 1H), MS (ESI, pos. ion) 7.94 (d, 1H), 7.43-7.38 (m, 2H), 7.16 (td, 1H), 6.04 (s, 1H), 4.24 (d, 1H), m/z: 494.9 [M + H]⁺ 4.06-3.97 (m, 2H), 3.84 (dd, 1H), 3.73-3.66 (m, 2H), 3.64-3.59 (m, 1H), 3.51 (s, 3H), 3.10-3.06 (m, 1H), 2.43-2.39 (m, 1H). X10 ¹H NMR (400 MHz, DMSO-d₆): δ 12.12 (s, 1H), 9.71 (s, 1H), 8.03 (d, 1H), MS (ESI, pos. ion) 7.96 (d, 1H), 7.44-7.38 (m, 2H), 7.18 (td, 1H), 6.02 (s, 1H), 3.94-3.82 (m, 3H), m/z: 522.9 [M + H]⁺ 3.62-3.54 (m, 2H), 3.53 (s, 3H), 2.78 (dd, 2H), 2.38-2.26 (m, 3H), 2.06-1.99 (m, 1H), 1.66-1.59 (m, 2H). X11 ¹H NMR (400 MHz, DMSO-d₆): δ 12.09 (br, 1H), 9.70 (s, 1H), 8.03 (d, 1H), MS (ESI, pos. ion) 7.94 (d, 1H), 7.44-7.38 (m, 2H), 7.18 (td, 1H), 6.04 (s, 1H), 3.95 (d, 1H), m/z: 523.2 [M + H]⁺ 3.86-3.81 (m, 2H), 3.57-3.54 (m, 1H), 3.52 (s, 3H), 3.50-3.47 (m, 1H), 2.87 (d, 1H), 2.62 (d, 1H), 2.35-2.19 (m, 3H), 2.14-2.08 (m, 1H), 1.73-1.61 (m, 2H). X12 ¹H NMR (400 MHz, DMSO-d₆): δ 9.87 (s, 1H), 8.03 (d, 1H), 7.94 (d, 1H), MS (ESI, pos. ion) 7.44-7.40 (m, 2H), 7.16 (td, 1H), 6.02 (s, 1H), 4.20 (d, 1H), 3.93 (d, 1H), m/z: 523.1 [M + H]⁺ 3.84-3.79 (m, 1H), 3.75-3.71 (m, 1H), 3.62-3.56 (m, 1H), 3.52 (s, 3H), 3.48-3.41 (m, 1H), 3.05-2.87 (m, 1H), 2.78-2.75 (m, 1H), 2.58-2.56 (m, 1H), 2.38-2.23 (m, 2H), 1.87-1.84 (m, 1H), 1.66-1.58 (m, 1H). X13 ¹H NMR (600 MHz, DMSO-d₆): δ 13.01 (s, 1H), 9.83 (s, 1H), 8.02 (d, 1H), MS (ESI, pos. ion) 7.93 (d, 1H), 7.42-7.38 (m, 2H), 7.17 (td, 1H), 6.02 (s, 1H), 4.07 (d, 1H), 3.89 (d, 1H), m/z: 508.7 [M + H]⁺ 3.76-3.62 (m, 3H), 3.51 (s, 3H), 3.47-3.43 (m, 1H), 2.98 (d, 1H), 2.89 (d, 1H), 1.20 (d, 3H). X14 ¹H NMR (400 MHz, DMSO-d₆): δ 12.11 (s, 1H), 9.76 (s, 1H), 8.02 (d, 1H), MS (ESI, pos. ion) 7.96 (d, 1H), 7.44-7.40 (m, 2H), 7.16 (td, 1H), 6.01 (s, 1H), 4.16 (d, 1H), 3.88 (d, 1H), m/z: 537.1 [M + H]⁺ 3.78-3.74 (m, 1H), 3.60-3.55 (m, 1H), 3.53 (s, 3H), 3.50-3.46 (m, 1H), 2.68 (d, 1H), 2.48-2.42 (m, 1H), 2.36-2.31 (m, 3H), 2.04-1.93 (m, 1H), 1.82-1.73 (m, 1H), 1.21 (d, 3H). X15 ¹H NMR (600 MHz, DMSO-d₆): δ 9.70 (br, 1H), 8.01 (d, 1H), 7.92 (d, 1H), MS (ESI, pos. ion) 7.44-7.38 (m, 2H), 7.18 (td, 1H), 6.01 (s, 1H), 4.31 (d, 1H), 4.09 (d, 1H), m/z: 515.1 [M + H]⁺ 3.94-3.89 (m, 1H), 3.53 (s, 3H), 3.48-3.44 (m, 1H), 3.23-3.07 (m, 2H), 2.84-2.75 (m, 1H). X16 ¹H NMR (400 MHz, DMSO-d₆): δ 12.07 (br, 1H), 9.55 (s, 1H), 7.99 (d, 1H), MS (ESI, pos. ion) 7.92 (d, 1H), 7.43-7.39 (m, 2H), 7.18 (td, 1H), 6.03 (s, 1H), 4.15 (d, 1H), 4.09 (d, 1H), m/z: 543.0 [M + H]⁺ 3.56-3.54 (m, 1H), 3.53 (s, 3H), 3.05-2.95 (m, 2H), 2.48-2.46 (m, 1H), 2.36-2.17 (m, 2H), 2.15-2.02 (m, 1H), 1.97-1.85 (m, 1H), 1.59-1.50 (m, 1H). X17 ¹H NMR (400 MHz, DMSO-d₆): δ 12.06 (br, 1H), 9.56 (s, 1H), 8.01 (d, 1H), MS (ESI, pos. ion) 7.94 (d, 1H), 7.44-7.40 (m, 2H), 7.16 (td, 1H), 6.05 (s, 1H), 4.13 (d, 1H), 4.09 (d, 1H), m/z: 543.0 [M + H]⁺ 3.57-3.54 (m, 1H), 3.52 (s, 3H), 3.06-2.96 (m, 2H), 2.47-2.45 (m, 1H), 2.37-2.17 (m, 2H), 2.16-2.02 (m, 1H), 1.98-1.85 (m, 1H), 1.60-1.51 (m, 1H).

In the specification, Unless specified or limited otherwise, terms such as “first” and “second” are used herein for purposes of description and are not intended to indicate or imply relative importance or significance.

Reference throughout this specification to “an embodiment,” “some embodiments,” “one embodiment”, “another example,” “an example,” “a specific examples,” or “some examples,” means that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the present disclosure. Thus, the appearances of the phrases such as “in some embodiments,” “in one embodiment”, “in an embodiment”, “in another example, “in an example,” “in a specific examples,” or “in some examples,” in various places throughout this specification are not necessarily referring to the same embodiment or example of the present disclosure. Furthermore, the particular features, structures, materials, or characteristics may be combined in any suitable manner in one or more embodiments or examples.

Although explanatory embodiments have been shown and described, it would be appreciated by those skilled in the art that the above embodiments cannot be construed to limit the present disclosure, and changes, alternatives, and modifications can be made in the embodiments without departing from spirit, principles and scope of the present disclosure. 

1. A process for preparing adihydropyrimidine compound having Formula (I), or a tautomer thereof having Formula (Ia),

wherein each R is F; R² is Cl or Br; R³ is C₁₋₄ alkyl; Z is —O—, —S—, —S(═O)_(t)—, or —N(R⁴)—; Y is —O—, —S—, —S(═O)_(t)—, —(CH₂)_(q)—, or —N(R⁵)—; each t and q is independently 0, 1, or 2; each of R⁴ and R⁵ is independently H or C₁₋₄ alkyl; each R⁶ is independently H, deuterium, halo, C₁₋₄ alkyl, C₁₋₄haloalkyl, amino, C₁₋₄alkylamino, C₁₋₄alkoxy, nitro, triazolyl, tetrazyl, —(CR⁷R^(7a))_(m)—OH, —S(═O)_(q)OR^(8a), —(CR⁷R^(7a))_(m)—S(═O)_(q)N(R^(8a))₂, —(CR⁷R^(7a))_(t)—N(R^(8a))₂, —(CR⁷R^(7a))_(m)—C(═O)O—R⁸, —(CR⁷R^(7a))_(m)—C(═O)O—(CR⁷R^(7a))_(m)—OC(═O)O—R⁸, —(CR⁷R^(7a))_(m)—C(═O)O—(CR⁷R^(7a))_(m)—OC(═O)—R⁸, —(CR⁷R^(7a))_(m)—C(═O)O—(CR⁷R^(7a))_(m)—C(═O)O—R⁸, —(CR⁷R^(7a))_(m)—OC(═O)—R⁸, or —(CR⁷R^(7a))_(m)—C(═O)—N(R⁸R^(8a)); each R^(7a) and R⁷ is independently H, halo, C₁₋₄ alkyl, C₁₋₄haloalkyl, —(CH₂)_(m)—OH, or —(CH₂)_(m)—C(═O)O—R⁸; or R^(7a) and R⁷, together with the carbon atom to which they are attached, form a C₃₋₆cycloalkyl group, C₂₋₉ heterocyclylgroup, or —(C═O)—; each R⁸ and R^(8a) is independently H, C₁₋₄ alkyl, amino-C₁₋₄-alkyl, C₁₋₄alkoxy, C₁₋₆ alkyl-S(═O)_(q)—, C₆₋₁₀ aryl, C₁₋₉heteroaryl, C₃₋₆cycloalkyl, C₂₋₉heterocyclyl, C₆₋₁₀ aryl-C₁₋₆-alkyl, C₁₋₉ heteroaryl-C₁₋₆-alkyl, C₃₋₆ cycloalkyl-C₁₋₄-alkyl, C₂₋₉ heterocyclyl-C₁₋₆-alkyl, C₂₋₉heterocyclyl-S(═O)_(q)—, C₁₋₉heteroaryl-S(═O)_(q)—, C₃₋₆cycloalkyl-S(═O)_(q)—, C₆₋₁₀ aryl-S(═O)_(q)—, —(CH₂)_(m)—OH, —(CH₂)_(m)—C(═O)O—(CH₂)_(m)—H, or —(CH₂)_(m)—OC(═O)—(CH₂)_(m)—H; each R⁹ is independently H, halo, C₁₋₄ alkyl, C₁₋₄haloalkyl, C₁₋₄ alkylthio, C₃₋₆cycloalkyl, —(CR⁷R^(7a))_(m)—C(═O)—N(R⁸R^(8a)), or —(CR⁷R^(7a))_(m)—C(═O)O—R⁸; R¹⁰ is H or deuterium; n is 0, 1, 2, 3, 4, or 5; each m is independently 0, 1, 2, 3, or 4; f is 1, 2, 3, or 4; and j is 0, 1, or 2; wherein the process comprises the steps of: step (A): reacting an amidine compound of Formula (II), or a salt thereof

with an aldehyde compound of Formula (III)

and a compound of Formula (IV)

to obtain a compound of Formula (V),

wherein R^(3b) is C₁₋₆alkoxy, C₁₋₆alkylamino, C₃₋₆cycloalkoxy, C₃₋₆cycloalkylamino, C₁₋₆ alkyl-C₃₋₆-cycloalkoxy, C₆₋₁₀arylamino, benzylamino, or benzyloxy; and R^(3a) is H or C₁₋₃ alkyl; step (B): halogenating the compound of Formula (V) to form a halide; and then reacting the halide with a compound of Formula (VI), or a salt thereof

to obtain a compound of Formula (VII),

step (C): forming the compound of Formula (I) or Formula (Ia) from the compound of Formula (VII) by means of a transesterification.
 2. The process of claim 1, wherein the dihydropyrimidine compound has Formula (I-1), or a tautomer thereof having Formula (Ia-1),

wherein each R⁶ is independently H, halo, C₁₋₄ alkyl, C₁₋₄haloalkyl, amino, C₁₋₄alkylamino, C₁₋₄alkoxy, nitro, triazolyl, tetrazyl, —(CR⁷R^(7a))_(m)—OH, —S(═O)_(q)OR^(8a), —(CR⁷R^(7a))_(m)—S(═O)N(R^(8a))₂, —(CR⁷R^(7a))_(t)—N(R^(8a))₂, —(CR⁷R^(7a))_(m)—C(═O)O—R⁸, —(CR⁷R^(7a))_(m)—C(═O)O—(CR⁷R^(7a))_(m)—OC(═O)O—R⁸, —(CR⁷R^(7a))_(m)—C(═O)O—(CR⁷R^(7a))_(m)—OC(═O)—R⁸, —(CR⁷R^(7a))_(m)—C(═O)O—(CR⁷R^(7a))_(m)—C(═O)O—R⁸, —(CR⁷R^(7a))_(m)—OC(═O)—R⁸, or —(CR⁷R^(7a))_(m)—C(═O)—N(R⁸R^(8a)); each R^(7a) and R⁷ is independently H, C₁₋₄ alkyl, C₁₋₄haloalkyl, —(CH₂)_(m)—OH, or —(CH₂)_(m)—C(═O)O—R⁸; and R^(3b) is C₁₋₆alkoxy, C₁₋₆alkylamino, benzylamino, or benzyloxy.
 3. The process of claim 2, wherein the dihydropyrimidine compound has Formula (I-2), or a tautomer thereof having Formula (Ia-2),

wherein R¹ is F; and R² is Cl or Br.
 4. The process of claim 1, wherein R³ is methyl, ethyl, propyl, isopropyl, tert-butyl, or butyl; Z is —O—, —S—, or —N(CH₃)—; Y is —O—, —S—, —S(═O)₂, or —(CH₂)_(q)—; each R⁶ is independently H, halo, C₁₋₄ alkyl, C₁₋₄haloalkyl, amino, C₁₋₄alkylamino, C₁₋₄alkoxy, nitro, triazolyl, tetrazyl, —(CR⁷R^(7a))_(m)—OH, —(CR⁷R^(7a))_(m)—C(═O)O—R⁸, —(CR⁷R^(7a))_(t)—N(R^(8a))₂, —S(═O)_(q)OR^(8a), —(CR⁷R^(7a))_(m)—S(═O)_(q)N(R^(8a))₂, —(CR⁷R^(7a))_(m)—C(═O)O—(CR⁷R^(7a))_(m)—OC(═O)O—R⁸, —(CR⁷R^(7a))_(m)—C(═O)O—(CR⁷R^(7a))_(m)—OC(═O)—R⁸, —(CR⁷R^(7a))_(m)—C(═O)O—(CR⁷R^(7a))_(m)—C(═O)O—R⁸, —(CR⁷R^(7a))_(m)—OC(═O)—R⁸, or —(CR⁷R^(7a))_(m)—C(═O)N(R⁸R^(8a)); each R^(7a) and R⁷ is independently H, methyl, ethyl, trifluoromethyl, —(CH₂)_(m)—OH, or —(CH₂)_(m)—C(═O)O—R⁸; each R⁸ and R^(8a) is independently H, methyl, ethyl, propyl, isopropyl, aminomethyl, methoxy, C₁₋₄ alkyl-S(═O)₂—, phenyl, pyridyl, thiazolyl, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyrimidinyl, pyridazinyl, diazolyl, triazolyl, tetrazolyl, thienyl, pyrazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyrazinyl, pyranyl, triazinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyl-S(═O)₂—, cyclobutyl-S(═O)₂—, cyclopentyl-S(═O)₂—, cyclohexyl-S(═O)₂—, naphthyl-S(═O)₂—, phenyl-S(═O)₂—, —(CH₂)_(m)—OH, —(CH₂)_(m)—C(═O)O—(CH₂)_(m)—H, or —(CH₂)_(m)—OC(═O)—(CH₂)_(m)—H; R^(3b) is methoxy, ethoxy, isopropoxy, propoxy, tert-butoxy, n-butoxy, 1-methylpropoxy, n-pentyloxy, n-hexyloxy, methylamino, ethylamino, isopropylamino, propylamino, tert-butylamino, n-butylamino, 1-methylpropylamino, n-pentylamino, n-hexylamino, benzylamino, or benzyloxy; and R^(3a) is H, methyl, ethyl, isopropyl, or propyl.
 5. The process of claim 1, wherein the reaction in step (A) is performed at a temperature from 25° C. to 154° C. or from 60° C. to 100° C.
 6. (canceled)
 7. The process of claim 1, wherein the step (A) further comprises a step of cooling the resulting compound of Formula (V) of step (A) to obtain a solid compound of Formula (V) at a cooling temperature from −40° C. to 40° C. or from 25° C. to 40° C.
 8. (canceled)
 9. The process of claim 7, wherein the cooling is performed for from 0 hour to 24 hours, or from 1 minute to 24 hours, or from 1 hour to 8 hours.
 10. (canceled)
 11. The process of claim 1, wherein the amidine compound of Formula (II) reacts with the aldehyde compound of Formula (III) and the compound of Formula (IV) in a first organic solvent, and the first organic solvent is applied in an amount of 1 equivalent to 80 equivalents, or 1 equivalent to 20 equivalents per 1 equivalent by weight of theamidine compound of Formula (II), or a salt thereof.
 12. (canceled)
 13. The process of claim 7, wherein step (A) further comprises a step of purifying the solid compound of Formula (V), wherein the solid compound of Formula (V) is purified by at least one of the following methods: (1) trituration, wherein the trituration is carried out at a temperature from −20° C. to 50° C. or from 5° C. to 40° C.; (2) recrystallization, wherein the recrystallization comprises a crystallization process at a temperature from −30° C. to 40° C. or from 0° C. to 40° C., and wherein the recrystallization comprises a crystallization process of from 1 hour to 20 hours or 1 hour to 12 hours; or (3) washing, wherein the washing is performed at a temperature from 0° C. to 30° C.
 14. (canceled)
 15. The process of claim 13, wherein the purification is carried out in a second organic solvent, and wherein the second organic solvent is applied in an amount of 2 equivalent to 20 equivalents per 1 equivalent by weight of the amidine compound of Formula (II), or a salt thereof. 16-23. (canceled)
 24. The process of claim 11, wherein each of the first organic solvent and the second organic solvent is independently a C₁₋₄ alcohol, a C₁₋₄ alcohol-water mixture, acetone, diethyl ether, isopropyl ether, petroleum ether, tetrahydrofuran, acetonitrile, cyclopentane, cyclohexane, n-hexane, C₁₋₄haloalkanes solvent, ethyl acetate, trifluoroethanol, 2-methoxyethanol, 1,2-dimethoxyethane, 2-methoxyethyl ether, N,N-dimethyl formamide, N-methylpyrolidone, or a combination thereof, or wherein each of the first organic solvent and the second organic solvent is independently methanol, ethanol, n-propanol, i-propanol, n-butanol, tert-butanol, an ethanol-water mixture at a volume ratio from 10:90 to 90:10, acetone, tetrahydrofuran, N-methylpyrolidone, trifluoroethanol, 2-methoxyethanol, 1,2-dimethoxyethane, 2-methoxyethyl ether, ethyl acetate, glycol, N,N-dimethyl formamide, or a combination thereof.
 25. (canceled)
 26. The process of claim 1, wherein the halogenating reaction in step (B) is carried out in a third organic solvent, and wherein the third organic solvent is one or more C₁₋₄ alcohols, one or more C₁₋₄haloalkanes, acetonitrile, isopropyl ether, petroleum ether, toluene, xylene, tetrahydrofuran, ethyl acetate, acetone, or a combination thereof, or wherein the third organic solvent is dichloromethane, chloroform, tetrachloromethane, acetonitrile, isopropyl ether, petroleum ether, tetrahydrofuran, methanol, ethanol, propanol, i-propanol, n-butanol, tert-butanol, ethyl acetate, acetone, or a combination thereof.
 27. (canceled)
 28. The process of claim 1, wherein the halogenating reaction in step (B) is carried out in the presence of a halogenating agent, and wherein the halogenating agent is N-bromosuccinimide, N-chlorosuccinimide, N-iodosuccinimide, 1,3-dibromo-5,5-dimethylhydantoin, or 1,3-dichloro-5,5-dimethylhydantoin, or a combination thereof.
 29. The process of claim 1, wherein the transesterification in step (C) is performed in the present of a base, and wherein the base is formed by reacting lithium, sodium, or potassium or a combination thereof with a C₁₋₄ alcohol.
 30. The process of claim 29, wherein the C₁₋₄ alcohol is methanol, ethanol, propanol, i-propanol, n-butanol, i-butanol, or tert-butanol, and wherein the lithium, sodium or potassium or a combination thereof is applied in an amount of 2 equivalents to 6 equivalents per 1 equivalent by mole of the compound of Formula (VII).
 31. (canceled)
 32. The process of claim 1, wherein the compound of Formula (IV) in step (A) is prepared by a process comprising reacting a compound of Formula (VIII) with a compound of Formula (IX),


33. A compound having Formula (V), or a tautomer thereof having Formula (V1), or a salt thereof, or a combination thereof,

wherein each R¹ is independently F; R² is Cl or Br; R^(3b) is C₁₋₆alkoxy, C₁₋₆alkylamino, C₃₋₆cycloalkoxy, C₃₋₆cycloalkylamino, C₁₋₆ alkyl-C₃₋₆-cycloalkoxy, C₆₋₁₀arylamino, benzylamino, or benzyloxy; R^(3a) is H or C₁₋₃ alkyl; each R⁹ is independently H, halo, C₁₋₄ alkyl, C₁₋₄alkylthio, C₁₋₄haloalkyl, C₃₋₆cycloalkyl, —(CR⁷R^(7a))_(m)—C(═O)—N(R⁸R^(8a)), or —(CR⁷R^(7a))_(m)—C(═O)O—R⁸; each R^(7a) and R⁷ is independently H, halo, C₁₋₄ alkyl, C₁₋₄haloalkyl, —(CH₂)_(m)—OH, or —(CH₂)_(m)—C(═O)O—R⁸; or R⁷ and R^(7a), together with the carbon atom to which they are attached, form a C₃₋₆cycloalkyl group, C₂₋₉ heterocyclylgroup, or —(C═O)—; each R⁸ and R^(8a) is independently H, C₁₋₄ alkyl, amino-C₁₋₄-alkyl, C₁₋₄alkoxy, C₁₋₆ alkyl-S(═O)_(q)—, C₆₋₁₀ aryl, C₁₋₉heteroaryl, C₃₋₆cycloalkyl, C₂₋₉heterocyclyl, C₆₋₁₀ aryl-C₁₋₆-alkyl, C₁₋₉ heteroaryl-C₁₋₆-alkyl, C₃₋₆ cycloalkyl-C₁₋₄-alkyl, C₂₋₉ heterocyclyl-C₁₋₆-alkyl, C₂₋₉heterocyclyl-S(═O)_(q)—, C₁₋₉heteroaryl-S(═O)_(q)—, C₃₋₆cycloalkyl-S(═O)_(q)—, C₆₋₁₀ aryl-S(═O)_(q)—, —(CH₂)_(m)—OH, —(CH₂)_(m)—C(═O)O—(CH₂)_(m)—H, or —(CH₂)_(m)—OC(═O)—(CH₂)_(m)—H; each m is independently 0, 1, 2, 3, or 4; R¹⁰ is H or deuterium; f is 1, 2, 3, or 4; Z is —O—, —S—, —S(═O)_(t), or —N(R⁴)—; each of j and t is independently 0, 1, or 2; and R⁴ is H or C₁₋₄ alkyl.
 34. The compound of claim 33 having Formula (V-1), or a tautomer thereof having Formula (V1-1), or a salt thereof, or a combination thereof,

wherein each R^(3b) is independently C₁₋₆alkoxy, C₁₋₆alkylamino, benzyloxy, or benzylamino.
 35. The compound of claim 33 having Formula (V-2), or a tautomer thereof having Formula (V1-2), or a salt thereof, or a combination thereof,

wherein R¹ is F; R² is Cl or Br; Z is —O—, —S—, or —N(CH₃)—; R^(3b) is methoxy, ethoxy, isopropoxy, propoxy, tert-butoxy, butoxy, 1-methylpropoxy, pentyloxy, hexyloxy, methylamino, ethylamino, isopropylamino, propylamino, tert-butylamino, butylamino, 1-methylpropylamino, pentylamino, hexylamino, benzylamino, or benzyloxy; and R^(3a) is H, methyl, ethyl, isopropyl, or propyl.
 36. A process for preparing adihydropyrimidine compound having Formula (I), or a tautomer thereof having Formula (Ia),

wherein each R¹ is F; R² is Cl or Br; R³ is C₁₋₄ alkyl; Z is —O—, —S—, —S(═O)_(t)—, or —N(R⁴)—; Y is —O—, —S—, —S(═O)_(t)—, —(CH₂)_(q)—, or —N(R⁵)—; each t and q is independently 0, 1, or 2; each of R⁴ and R⁵ is independently H or C₁₋₄ alkyl; each R⁶ is independently H, deuterium, halo, C₁₋₄ alkyl, C₁₋₄haloalkyl, amino, C₁₋₄alkylamino, C₁₋₄alkoxy, nitro, triazolyl, tetrazyl, —(CR⁷R^(7a))_(m)—OH, —(CR⁷R^(7a))_(m)—C(═O)O—R⁸, —(CR⁷R^(7a))_(t)—N(R^(8a))₂, —S(═O)_(q)OR^(8a), —(CR⁷R^(7a))_(m)—S(═O)_(q)N(R^(8a))₂, —(CR⁷R^(7a))_(m)—C(═O)O—(CR⁷R^(7a))_(m)—OC(═O)O—R⁸, —(CR⁷R^(7a))_(m)—C(═O)O—(CR⁷R^(7a))_(m)—OC(═O)—R⁸, —(CR⁷R^(7a))_(m)—C(═O)O—(CR⁷R^(7a))_(m)—C(═O)O—R⁸, —(CR⁷R^(7a))_(m)—OC(═O)—R⁸, or —(CR⁷R^(7a))_(m)—C(═O)—N(CR⁸R^(8a)); each R^(7a) and R⁷ is independently H, halo, C₁₋₄ alkyl, C₁₋₄haloalkyl, —(CH₂)_(m)—OH, or —(CH₂)_(m)—C(═O)O—R⁸, or R^(7a) and R⁷, together with the carbon atom to which they are attached, form a C₃₋₆cycloalkyl group, C₂₋₉ heterocyclylgroup, or —(C═O)—; each R⁸ and R^(8a) is independently H, C₁₋₄ alkyl, amino-C₁₋₄-alkyl, C₁₋₄alkoxy, C₁₋₆ alkyl-S(═O)_(q)—, C₆₋₁₀ aryl, C₁₋₉heteroaryl, C₃₋₆cycloalkyl, C₂₋₉heterocyclyl, C₆₋₁₀ aryl-C₁₋₆-alkyl, C₁₋₉ heteroaryl-C₁₋₆-alkyl, C₃₋₆ cycloalkyl-C₁₋₄-alkyl, C₂₋₉ heterocyclyl-C₁₋₆-alkyl, C₂₋₉heterocyclyl-S(═O)_(q)—, C₁₋₉heteroaryl-S(═O)_(q)—, C₃₋₆cycloalkyl-S(═O)_(q)—, C₆₋₁₀ aryl-S(═O)_(q)—, —(CH₂)_(m)—OH, —(CH₂)_(m)—C(═O)O—(CH₂)_(m)—H, or —(CH₂)_(m)—OC(═O)—(CH₂)_(m)—H; each R⁹ is independently H, halo, C₁₋₄ alkyl, C₁₋₄ alkylthio, C₁₋₄haloalkyl, C₃₋₆cycloalkyl, —(CR⁷R^(7a))_(m)—C(═O)—N(R⁸R^(8a)), or —(CR⁷R^(7a))_(m)—C(═O)O—R⁸; R¹⁰ is H or deuterium; n is 0, 1, 2, 3, 4, or 5; each m is independently 0, 1, 2, 3, or 4; f is 1, 2, 3, or 4; and j is 0, 1, or 2; wherein the process comprises the steps of: step (1): reacting an amidine compound of Formula (II), or a salt thereof

with an aldehyde compound of Formula (III)

and a compound of Formula (IV)

to obtain a compound of Formula (V),

step(2): forming a compound of Formula (X) from the compound of Formula (V) by means of a transesterification,

wherein R^(3b) is C₁₋₆alkoxy, C₁₋₆alkylamino, C₃₋₆cycloalkoxy, C₃₋₆-cycloalkylamino, C₁₋₆ alkyl-C₃₋₆-cycloalkoxy, C₆₋₁₀arylamino, benzylamino, or benzyloxy; and R^(3a) is H or C₁₋₃ alkyl; and step (3): halogenating the compound of Formula (X) to form a halide; and then reacting the halide with a compound of Formula (VI), or a salt thereof to obtain a compound of Formula (I) or Formula (Ia),


37. The process of claim 36, wherein the dihydropyrimidine compound has Formula (I-1), or a tautomer thereof having Formula (Ia-1),

wherein each R⁶ is independently H, halo, C₁₋₄ alkyl, C₁₋₄haloalkyl, amino, C₁₋₄alkylamino, C₁₋₄alkoxy, nitro, triazolyl, tetrazyl, —(CR⁷R^(7a))_(m)—OH, —(CR⁷R^(7a))_(m)—C(═O)O—R⁸, —(CR⁷R^(7a))_(t)—N(R^(8a))₂, —S(═O)_(q)OR^(8a), —(CR⁷R^(7a))_(m)—S(═O)_(q)N(R^(8a))₂, —(CR⁷R^(7a))_(m)—C(═O)O—(CR⁷R^(7a))_(m)—OC(═O)O—R⁸, —(CR⁷R^(7a))_(m)—C(═O)O—(CR⁷R^(7a))_(m)—OC(═O)—R⁸, —(CR⁷R^(7a))_(m)—C(═O)O—(CR⁷R^(7a))_(m)—C(═O)O—R⁸, —(CR⁷R^(7a))_(m)—OC(═O)—R⁸, or —(CR⁷R^(7a))_(m)—C(═O)—N(R⁸R^(8a)); and each R^(7a) and R⁷ is independently H, C₁₋₄ alkyl, C₁₋₄haloalkyl, —(CH₂)_(m)—OH, or —(CH₂)_(m)—C(═O)O—R⁸; R^(3b) is C₁₋₆alkoxy, C₁₋₆alkylamino, benzylamino, or benzyloxy.
 38. The process of claim 37, wherein the dihydropyrimidine compound has Formula (I-2), or a tautomer thereof having Formula (Ia-2),

wherein R¹ is F; and R² is Cl or Br.
 39. The process of claim 36, wherein R³ is methyl, ethyl, propyl, isopropyl, tert-butyl, or butyl; Z is —O—, —S—, or, —N(CH₃)—; Y is —O—, —S—, —S(═O)₂, or —(CH₂)_(q)—; each R⁶ is independently H, halo, C₁₋₄ alkyl, C₁₋₄haloalkyl, amino, C₁₋₄alkylamino, C₁₋₄alkoxy, nitro, triazolyl, tetrazyl, —(CR⁷R^(7a))_(m)—OH, —S(═O)_(q)OR^(8a), —(CR⁷R^(7a))_(m)—S(═O)_(q)N(R^(8a))₂, —(CR⁷R^(7a))_(t)—N(R^(8a))₂, —(CR⁷R^(7a))_(m)—C(═O)O—R⁸, —(CR⁷R^(7a))_(m)—C(═O)O—(CR⁷R^(7a))_(m)—OC(═O)O—R⁸, —(CR⁷R^(7a))_(m)—C(═O)O—(CR⁷R^(7a))_(m)—OC(═O)—R⁸, —(CR⁷R^(7a))_(m)—C(═O)O—(CR⁷R^(7a))_(m)—C(═O)O—R⁸, —(CR⁷R^(7a))_(m)—OC(═O)—R⁸, or —(CR⁷R^(7a))_(m)—C(═O)N(R⁸R^(8a)); each R^(7a) and R⁷ is independently H, methyl, ethyl, trifluoromethyl, —(CH₂)_(m)—OH, or —(CH₂)_(m)—C(═O)O—R⁸; each R⁸ and R^(8a) is independently H, methyl, ethyl, propyl, isopropyl, aminomethyl, methoxy, C₁₋₄ alkyl-S(═O)₂—, phenyl, pyridyl, thiazolyl, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyrimidinyl, pyridazinyl, diazolyl, triazolyl, tetrazolyl, thienyl, pyrazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyrazinyl, pyranyl, triazinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyl-S(═O)₂—, cyclobutyl-S(═O)₂—, cyclopentyl-S(═O)₂—, cyclohexyl-S(═O)₂—, naphthyl-S(═O)₂—, phenyl-S(═O)₂—, —(CH₂)_(m)—OH, —(CH₂)_(m)—C(═O)O—(CH₂)_(m)—H, or —(CH₂)_(m)—OC(═O)—(CH₂)_(m)—H; R^(3b) is methoxy, ethoxy, isopropoxy, propoxy, tert-butoxy, n-butoxy, 1-methylpropoxy, n-pentyloxy, n-hexyloxy, methylamino, ethylamino, isopropylamino, propylamino, tert-butylamino, n-butylamino, 1-methylpropylamino, n-pentylamino, n-hexylamino, benzylamino, or benzyloxy; and R^(3a) is H, methyl, ethyl, isopropyl, or propyl. 40-60. (canceled)
 61. The process of claim 36, wherein the transesterification in step (2) is performed in the present of a base, wherein the base is formed by reacting lithium, sodium, or potassium or a combination thereof with the C₁₋₄ alcohol, wherein the C₁₋₄ alcohol is methanol, ethanol, propanol, i-propanol, n-butanol, i-butanol, or tert-butanol, and wherein the lithium, sodium, potassium or a combination thereof is applied in an amount of 2 equivalents to 8 equivalents per 1 equivalent by mole of the compound of Formula (V). 62-63. (canceled)
 64. The process of claim 36, wherein the halogenating reaction in step (3) is carried out in a forth organic solvent, and wherein the forth organic solvent is one or more C₁₋₄ alcohols, one or more C₁₋₄haloalkanes, ethyl acetate, acetonitrile, isopropyl ether, petroleum ether, toluene, xylene, tetrahydrofuran, acetone, or a combination thereof, or the forth organic solvent is methanol, ethanol, propanol, i-propanol, n-butanol, tert-butanol, dichloromethane, chloroform, tetrachloromethane, ethyl acetate, acetonitrile, isopropyl ether, petroleum ether, tetrahydrofuran, acetone, or a combination thereof.
 65. (canceled)
 66. The process of claim 36, wherein the halogenating reaction in step (3) is carried out in the presence of a halogenating agent, and wherein the halogenating agent is N-bromosuccinimide, N-chlorosuccinimide, N-iodosuccinimide, 1,3-dibromo-5,5-dimethylhydantoin, 1,3-dichloro-5,5-dimethylhydantoin, or a combination thereof.
 67. The process of claim 15, wherein each of the first organic solvent and the second organic solvent is independently a C1-4 alcohol, a C1-4 alcohol-water mixture, acetone, diethyl ether, isopropyl ether, petroleum ether, tetrahydrofuran, acetonitrile, cyclopentane, cyclohexane, n-hexane, C1-4haloalkanes solvent, ethyl acetate, trifluoroethanol, 2-methoxyethanol, 1,2-dimethoxyethane, 2-methoxyethyl ether, N,N-dimethyl formamide, N-methylpyrolidone, or a combination thereof, or wherein each of the first organic solvent and the second organic solvent is independently methanol, ethanol, n-propanol, i-propanol, n-butanol, tert-butanol, an ethanol-water mixture at a volume ratio from 10:90 to 90:10, acetone, tetrahydrofuran, N-methylpyrolidone, trifluoroethanol, 2-methoxyethanol, 1,2-dimethoxyethane, 2-methoxyethyl ether, ethyl acetate, glycol, N,N-dimethyl formamide, or a combination thereof. 